Transcutaneous analyte sensor

ABSTRACT

A transcutaneous sensor device configured for continuously measuring analyte concentrations in a host is provided. In some embodiments, the transcutaneous sensor device 100 comprises an in vivo portion 160 configured for insertion under the skin 180 of the host and an ex vivo portion 170 configured to remain above the surface of the skin 180 of the host after sensor insertion of the in vivo portion. The in vivo portion may comprise a tissue piercing element 110 configured for piercing the skin 180 of the host and a sensor body 120 comprising a material or support member 130 that provides sufficient column strength to allow the sensor body to be pushable in a host tissue without substantial buckling. The ex vivo portion 170 may be configured to comprise (or operably connect to) a sensor electronics unit and may comprise a mounting unit 150. Also described here are various configurations of the sensor body and the tissue piercing element that may be used to protect the membrane of the sensor body.

INCORPORATION BY REFERENCE TO RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. This application is a continuation of U.S. application Ser.No. 12/893,850, filed on Sep. 29, 2010, which claims the benefit ofpriority under 35 U.S.C. § 119(e) to Provisional Application No.61/247,463, filed on Sep. 30, 2009. Each of the aforementionedapplications is incorporated by reference herein in its entirety, andeach is hereby expressly made a part of this specification.

FIELD OF THE INVENTION

The embodiments described herein relate generally to analyte sensors.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a chronic disease, which occurs when the pancreasdoes not produce enough insulin (Type I), or when the body cannoteffectively use the insulin it produces (Type II). This conditiontypically leads to an increased concentration of glucose in the blood(hyperglycemia), which can cause an array of physiological derangements(e.g., kidney failure, skin ulcers, or bleeding into the vitreous of theeye) associated with the deterioration of small blood vessels. Or, ahypoglycemic reaction (low blood sugar) is induced by an inadvertentoverdose of insulin, or after a normal dose of insulin orglucose-lowering agent accompanied by extraordinary exercise orinsufficient food intake.

A variety of transcutaneous sensor devices have been developed forcontinuously measuring blood glucose concentrations. Typically, thesetypes of sensor devices employ an applicator or other similar insertiontool for inserting a transcutaneous sensor under a host's skin.Conventionally, the applicator comprises a plunger and a needle formedwith a lumen configured to receive the sensor. Because of the additionalparts (e.g., an applicator with a plunger) and steps (e.g., a sensorunit retraction step) required for sensor deployment, use of a separateapplicator or other similar tools for sensor insertion can becumbersome, or difficult, particularly for a new user.

SUMMARY OF THE INVENTION

In a first aspect, a sensor device is provided for measuring an analyteconcentration, the sensor device comprising: a sensor unit comprising atissue piercing element and a sensor body, the sensor body comprising atleast one electrode and a membrane covering at least a portion of the atleast one electrode, wherein the sensor unit is configured to have acolumn strength sufficient to allow the sensor unit to be insertedthrough a skin of a host without substantial buckling; and a mountingunit configured to support the sensor device on an exterior surface ofthe skin of the host.

In an embodiment of the first aspect, the sensor unit is configured tohave a length that allows for at least a portion of the sensor body toreside within a stratum germinativum of the skin, e.g., from about 0.1mm to about 1.5 mm.

In an embodiment of the first aspect, the sensor unit is configured tohave a length that allows for at least a portion of the sensor body toreside within a dermis of the skin, e.g., from about 1 mm to about 7 mm.

In an embodiment of the first aspect, the sensor unit is configured tohave a length that allows for at least a portion of the sensor body toreside within a subcutaneous layer of the skin, e.g., from about 3 mm toabout 10 mm.

In an embodiment of the first aspect, the tissue piercing element isconfigured to protect the membrane from damage during insertion of thesensor unit.

In an embodiment of the first aspect, the tissue piercing element isconfigured to withstand an axial load greater than about 1 Newtonwithout substantial buckling.

In an embodiment of the first aspect, the tissue piercing elementcomprises at least one material selected from the group consisting ofmetals, ceramics, semiconductors, organics, polymers, composites, andcombinations thereof.

In an embodiment of the first aspect, a largest dimension of a crosssection transverse to a longitudinal axis of the tissue piercing elementis greater than a largest dimension of a cross section transverse to alongitudinal axis of the sensor body.

In an embodiment of the first aspect, a largest dimension of a crosssection transverse to a longitudinal axis of the tissue piercing elementis less than about 0.1 mm.

In an embodiment of the first aspect, a largest dimension of a crosssection transverse to a longitudinal axis of the sensor body is lessthan about 0.05 mm.

In an embodiment of the first aspect, the at least one electrodecomprises a working electrode and a reference electrode.

In an embodiment of the first aspect, the sensor body further comprisesa support member configured to protect the membrane from damage duringinsertion of the sensor unit.

In an embodiment of the first aspect, the support member comprises atleast one material selected from the group consisting of stainlesssteel, titanium, tantalum, platinum, platinum-iridium, iridium,polymers, ceramics, composites, and combinations thereof.

In an embodiment of the first aspect, the support member is configuredto withstand an axial load greater than about 1 Newton withoutsubstantial buckling.

In an embodiment of the first aspect, the at least one electrode formsthe support member.

In an embodiment of the first aspect, the support member is configuredto support at least a portion of the at least one electrode.

In an embodiment of the first aspect, the support member is configuredto partially surround the at least one electrode.

In an embodiment of the first aspect, the support member is configuredto substantially surround the at least one electrode.

In an embodiment of the first aspect, the support member comprises atleast one window portion configured to allow passage of a biologicalfluid to the membrane.

In an embodiment of the first aspect, the mounting unit comprises aguiding portion configured to provide guidance and enhance a columnstrength of the sensor unit as the sensor unit is inserted through theskin.

In an embodiment of the first aspect, the mounting unit comprises asensor electronics unit operatively connected to the sensor body.

In an embodiment of the first aspect, the sensor electronics unit isconnected to the sensor body via contacts configured to providemechanical and electrical connection between the sensor electronics unitand the sensor body

In an embodiment of the first aspect, the sensor body is directlyhardwired to the sensor electronics unit.

In an embodiment of the first aspect, the sensor electronics unit isconfigured to be located over a sensor insertion site.

In an embodiment of the first aspect, the sensor electronics unit isconfigured to be detachably connected to the mounting unit via atethered connection

In an embodiment of the first aspect, the sensor electronics unit isconfigured to be releasably attached to the mounting unit.

In an embodiment of the first aspect, the mounting unit comprises acolor display element configured to display at least one of a firstcolor when analyte concentration is below a preselected target range, asecond color when analyte concentration is within a preselected targetrange, or a third color when analyte concentration is above apreselected target range.

In an embodiment of the first aspect, the color display element isconfigured to display a color gradation that represents a degree ofchange in an analyte concentration.

In an embodiment of the first aspect, the mounting unit comprises a userinterface.

In an embodiment of the first aspect, the user interface is configuredto display a representation of a range of analyte values that areassociated with an analyte concentration.

In an embodiment of the first aspect, the user interface is configuredto display a directional trend of the analyte concentration.

In an embodiment of the first aspect, the user interface is configuredto display at least one graphical illustration indicating at least onearea of increasing clinical risk.

In an embodiment of the first aspect, the user interface is configuredto change at least one of colors or illustrations that represent anearness to a clinical risk.

In a second aspect, a device is provided for measuring an analyteconcentration in a host, the device comprising: a sensor configured forpress insertion through a skin of a host, the sensor comprising at leastone electrode, a membrane covering at least a portion of the at leastone electrode, and a distal tip configured for piercing tissue, whereinthe at least one electrode has sufficient column strength to allow thesensor to be inserted through the skin of the host without substantialbuckling.

In an embodiment of the second aspect, the sensor is configured to havea length that allows for at least a portion of the at least oneelectrode to reside within a stratum germinativum of the skin, e.g.,from about 0.2 mm to about 1.5 mm.

In an embodiment of the second aspect, the sensor is configured to havea length that allows for at least a portion of the at least oneelectrode to reside within a dermis of the skin, e.g., from about 1 mmto about 7 mm.

In an embodiment of the second aspect, the sensor is configured to havea length that allows for at least a portion of the at least oneelectrode to reside within a subcutaneous layer of the skin, e.g., fromabout 3 mm to about 10 mm.

In an embodiment of the second aspect, the distal tip is configured toprotect the membrane from damage during insertion of the sensor.

In an embodiment of the second aspect, the sensor is configured towithstand an axial load greater than about 1 Newton without substantialbuckling.

In an embodiment of the second aspect, the distal tip comprises at leastone material selected from the group consisting of metals, ceramics,semiconductors, organics, polymers, composites, and combinationsthereof.

In an embodiment of the second aspect, wherein a largest dimension of across section transverse to a longitudinal axis of the distal tip isgreater than a largest dimension of a cross section transverse to alongitudinal axis of the at least one electrode.

In an embodiment of the second aspect, a largest dimension of a crosssection transverse to a longitudinal axis of the distal tip is less thanabout 0.1 mm.

In an embodiment of the second aspect, a largest dimension of a crosssection transverse to a longitudinal axis of the at least one electrodeis less than about 0.05 mm.

In an embodiment of the second aspect, the at least one electrodecomprises a working electrode and a reference electrode.

In an embodiment of the second aspect, the at least one electrodecomprises at least one material selected from the group consisting ofstainless steel, titanium, tantalum, platinum, platinum-iridium,iridium, polymers, ceramics, composites, and combinations thereof.

In an embodiment of the second aspect, the at least one electrode isconfigured to withstand an axial load greater than about 1 Newtonwithout substantial buckling.

In a third aspect, a sensor device is provided for measuring an analyteconcentration in a host, the sensor device comprising: at least oneelectrode comprising a distal end, an electroactive surface, and amembrane located over at least a portion of the electroactive surface,the membrane configured to limit transport of analyte to theelectroactive surface; and a tip portion attached to the distal end ofthe at least one electrode and configured to pierce tissue; wherein alargest dimension of a cross section transverse to a longitudinal axisof the tip portion is greater than a largest dimension of a crosssection transverse to a longitudinal axis of the at least one electrode.

In an embodiment of the third aspect, the sensor device is configured tohave a length allowing for at least a portion of the at least oneelectrode to reside within a stratum germinativum of the skin.

In an embodiment of the third aspect, the sensor device is configured tohave a length allowing for at least a portion of the at least oneelectrode to reside within a dermis of the skin.

In an embodiment of the third aspect, the sensor device is configured tohave a length allowing for at least a portion of the at least oneelectrode to reside within a subcutaneous layer of the skin.

In an embodiment of the third aspect, the tip portion is configured toprotect the membrane from damage during insertion of the sensor device.

In an embodiment of the third aspect, the tip portion is configured towithstand an axial load greater than about 1 Newton without substantialbuckling.

In an embodiment of the third aspect, the tip portion comprises at leastone material selected from the group consisting of metals, ceramics,semiconductors, organics, polymers, composites, and combinationsthereof.

In an embodiment of the third aspect, the largest dimension of the crosssection transverse to the longitudinal axis of the tip portion is lessthan about 0.1 mm.

In an embodiment of the third aspect, the largest dimension of the crosssection transverse to the longitudinal axis of the at least oneelectrode is less than about 0.05 mm.

In an embodiment of the third aspect, the at least one electrodecomprises a working electrode and a reference electrode.

In an embodiment of the third aspect, the at least one electrodecomprises at least one material selected from the group consisting ofstainless steel, titanium, tantalum, platinum, platinum-iridium,iridium, polymers, ceramics, composites, and combinations thereof.

In an embodiment of the third aspect, the at least one electrode isconfigured to withstand an axial load greater than about 1 Newtonwithout substantial buckling.

In a fourth aspect, a sensor device is provided for measuring an analyteconcentration in a host, the sensor device comprising: a tissue piercingelement; a sensor comprising at least one electrode configured tomeasure a concentration of analyte in a host and a membrane disposedover at least a portion of the at least one electrode and configured tolimit transport of analyte to the at least one electrode; and a supportmember configured to substantially surround the sensor, the supportmember comprising at least one opening configured to allow passage of abiological fluid to the membrane.

In an embodiment of the fourth aspect, the tissue piercing element isconfigured to protect the membrane from damage during insertion of thesensor device.

In an embodiment of the fourth aspect, the tissue piercing element isconfigured to withstand an axial load greater than about 1 Newtonwithout substantial buckling.

In an embodiment of the fourth aspect, the tissue piercing elementcomprises at least one material selected from the group consisting ofmetals, ceramics, semiconductors, organics, polymers, composites, andcombinations thereof.

In an embodiment of the fourth aspect, the at least one electrodecomprises a working electrode and a reference electrode.

In an embodiment of the fourth aspect, the support member comprises atleast one material selected from the group consisting of stainlesssteel, titanium, tantalum, platinum, platinum-iridium, iridium,polymers, ceramics, composites, and combinations thereof.

In an embodiment of the fourth aspect, the support member is configuredto withstand an axial load greater than about 1 Newton withoutsubstantial buckling.

In a fifth aspect, a device for measuring an analyte concentration in ahost is provided, the device comprising: a sensor unit comprising adistal tip and a sensor body comprising an electrode body and a membranedisposed over at least a portion of the electrode body, the electrodebody comprising at least one material providing the electrode body withsufficient column strength to allow the sensor body to be insertedthrough a skin of a host without substantial buckling; and a mountingunit adapted to receive a pressure from a user for insertion of thesensor unit through the skin.

In an embodiment of the fifth aspect, the distal tip is configured toprotect the membrane from damage during insertion of the sensor body.

In an embodiment of the fifth aspect, the distal tip is configured towithstand an axial load greater than about 1 Newton without substantialbuckling.

In an embodiment of the fifth aspect, the distal tip comprises at leastone material selected from the group consisting of metals, ceramics,semiconductors, organics, polymers, composites, and combinationsthereof.

In an embodiment of the fifth aspect, the at least one electrode bodycomprises a working electrode and a reference electrode.

In an embodiment of the fifth aspect, the electrode body comprises atleast one material selected from the group consisting of stainlesssteel, titanium, tantalum, platinum, platinum-iridium, iridium,polymers, ceramics, composites, and combinations thereof.

In an embodiment of the fifth aspect, the electrode body is configuredto withstand an axial load greater than about 1 Newtons withoutsubstantial buckling.

In an embodiment of the fifth aspect, the mounting unit comprises aguiding portion configured to provide guidance and enhance the columnstrength of the sensor body as the sensor body is inserted through theskin.

In an embodiment of the fifth aspect, the mounting unit comprises asensor electronics unit operatively connected to the sensor body.

In an embodiment of the fifth aspect, the sensor electronics unit isconnected to the sensor body via contacts configured to providemechanical and electrical connection between the sensor electronics unitand the sensor body

In an embodiment of the fifth aspect, the sensor body is directlyhardwired to the sensor electronics unit.

In an embodiment of the fifth aspect, the sensor electronics unit isconfigured to be located over a sensor insertion site.

In an embodiment of the fifth aspect, the sensor electronics unit isconfigured to be detachably connected to the mounting unit via atethered connection

In an embodiment of the fifth aspect, the sensor electronics unit isconfigured to be releasably attached to the mounting unit.

In an embodiment of the fifth aspect, the sensor unit is configured tobe in a retracted state hidden inside the mounting unit prior toinsertion of the sensor unit.

In an embodiment of the fifth aspect, the mounting unit comprises acolor display element configured to display at least one of a firstcolor when analyte concentration is below a preselected target range, asecond color when analyte concentration is within a preselected targetrange, or a third color when analyte concentration is above apreselected target range.

In an embodiment of the fifth aspect, the color display element isconfigured to display a color gradation that represents a degree ofchange in analyte concentration.

In an embodiment of the fifth aspect, the mounting unit comprises a userinterface.

In an embodiment of the fifth aspect, the user interface is configuredto display a representation of a range of analyte values that areassociated with analyte concentration.

In an embodiment of the fifth aspect, the user interface is configuredto display a directional trend of the analyte concentration.

In an embodiment of the fifth aspect, the user interface is configuredto display at least one graphical illustration indicating at least onearea of increasing clinical risk.

In an embodiment of the fifth aspect, the user interface is configuredto change at least one of colors or illustrations that represent anearness to a clinical risk.

In a sixth aspect, a sensor array for measuring an analyte concentrationis provided, the sensor array comprising: a laminate comprising anadhesive layer configured for adhering the laminate to a skin of a host;and a plurality of sensor devices, each comprising a tissue piercingelement configured for piercing tissue and a sensor with anenzyme-containing membrane, wherein the plurality of sensor devices areeach attached to the laminate and are each configured for insertionthrough the skin at a different insertion site.

In an embodiment of the sixth aspect, the laminate comprises sensorelectronics operatively connected to the sensor body.

In an embodiment of the sixth aspect, the laminate comprises atransmitter configured to transmit sensor data to a remote computersystem.

In an embodiment of the sixth aspect, the plurality of sensor devices isconfigured to provide parallel measurements of analyte concentration.

In an embodiment of the sixth aspect, the plurality of sensor devicescomprise a first sensor device and a second sensor device, wherein thefirst sensor device comprises a first sensor configured to measureanalyte concentration at a first range of analyte concentrations and thesecond sensor device comprises a second sensor configured to measureanalyte concentration at a second range of analyte concentrations, andwherein the first range is different from the second range.

In an embodiment of the sixth aspect, the plurality of sensor devicescomprise a first sensor device and a second sensor device, wherein thefirst sensor device comprises a first sensor configured to reside in ahost tissue at a first depth and a second sensor configured to reside inthe host tissue at a second depth, and wherein the first depth isdifferent from the second depth.

In an embodiment of the sixth aspect, the sensors and tissue piercingelements of the plurality of sensor devices are each configured to havesufficient column strength to allow for insertion through the skinwithout substantial buckling.

In an embodiment of the sixth aspect, the tissue piercing element isconfigured to protect the enzyme-containing membrane from damage duringinsertion of the sensor.

In an embodiment of the sixth aspect, each of the plurality of sensordevices further comprises a support member configured to substantiallysurround the sensor, the support member comprising at least one openingconfigured to allow passage of a biological fluid to theenzyme-containing membrane.

In an embodiment of the sixth aspect, the plurality of sensor devicescomprise a first sensor device and a second sensor device, wherein thefirst sensor device comprises working electrode and the second sensorcomprises a reference electrode.

In an embodiment of the sixth aspect, each of the plurality of sensordevices comprises a working electrode and a reference electrode.

In a seventh aspect, a sensor device for measuring an analyteconcentration is provided, the sensor device comprising: a sensor unitcomprising an in vivo portion having a tissue piercing element and asensor body, the sensor body comprising at least one electrode and amembrane covering at least a portion of the at least one electrode; anda mounting unit configured to support the sensor device on an exteriorsurface of a host's skin.

In an embodiment of the seventh aspect, the mounting unit comprises aguiding portion configured to guide insertion of the in vivo portion ofthe sensor unit through the host's skin and to support a column strengthof the sensor unit such that the in vivo portion is capable of beinginserted through the host's skin without substantial buckling; andwherein the guiding portion is configured to remain ex vivo duringinsertion of the in vivo portion of the sensor unit.

In an embodiment of the seventh aspect, the tissue piercing element,with the support of the guiding portion, is capable of withstanding anaxial load greater than about 1 Newton without substantial buckling.

In an embodiment of the seventh aspect, the tissue piercing element isconfigured to protect the membrane from damage during insertion of thein vivo portion of the sensor unit.

In an embodiment of the seventh aspect, a largest dimension of a crosssection transverse to a longitudinal axis of the tissue piercing elementis greater than a largest dimension of a cross section transverse to alongitudinal axis of the sensor body.

In an embodiment of the seventh aspect, the at least one electrodecomprises a working electrode and a reference electrode.

In an embodiment of the seventh aspect, the sensor body furthercomprises a support member configured to protect the membrane fromdamage during insertion of the sensor unit.

In an embodiment of the seventh aspect, the at least one electrode is asupport member.

In an embodiment of the seventh aspect, the support member, with thesupport of a guiding member of the mounting unit, is capable ofwithstanding an axial load greater than about 1 Newton withoutsubstantial buckling.

In an embodiment of the seventh aspect, the support member is configuredto support at least a portion of the at least one electrode.

In an embodiment of the seventh aspect, the support member is configuredto substantially surround the at least one electrode.

In an embodiment of the seventh aspect, the mounting unit comprises asensor electronics unit operatively and detachably connected to thesensor body.

In an embodiment of the seventh aspect, the sensor electronics unit isconfigured to be located over a sensor insertion site.

In an eighth embodiment, a sensor array for measuring an analyteconcentration is provided, the sensor array comprising: a laminatecomprising an adhesive layer configured for adhering the laminate to ahost's skin; and a plurality of sensor devices each attached to thelaminate and each configured for insertion through the skin at adifferent insertion site, wherein each sensor device comprises a sensorunit and a mounting unit configured to support the sensor device on anexterior surface of the host's skin, the sensor unit comprising an invivo portion having a tissue piercing element and a sensor body, thesensor body comprising at least one electrode and a membrane covering atleast a portion of the at least one electrode.

In an embodiment of the eighth aspect, the laminate comprises sensorelectronics operatively connected to the sensor devices.

In an embodiment of the eighth aspect, the plurality of sensor devicesis configured to provide parallel measurements of analyte concentration.

In an embodiment of the eighth aspect, the plurality of sensor devicescomprises a first sensor device and a second sensor device, wherein thefirst sensor device is configured to measure analyte concentration at afirst range of analyte concentrations and the second sensor device isconfigured to measure analyte concentration at a second range of analyteconcentrations, wherein the first range is different from the secondrange.

In an embodiment of the eighth aspect, the plurality of sensor devicescomprises a first sensor device and a second sensor device, wherein thefirst sensor device comprises a first sensor body configured to residein a host tissue at a first depth, wherein the second sensor devicecomprises a second sensor body configured to reside in the host tissueat a second depth, and wherein the first depth is different from thesecond depth.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a schematic side view of one embodiment of the sensordevice.

FIGS. 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H illustrate side views ofdifferent embodiments of distal tips of the tissue piercing element.

FIG. 3A illustrates a perspective view of another embodiment of thesensor device without a sensor embedded therein; FIG. 3B illustrates aperspective view of the embodiment of FIG. 3A with a sensor embeddedtherein; FIG. 3C illustrates a perspective view of another embodiment ofthe sensor device; FIG. 3D illustrates a side view of another embodimentof the tissue piercing element; and FIG. 3E illustrates one embodiment,in which a sensor electronics unit is adapted to be united with amounting unit.

FIG. 4 illustrates an expanded cutaway view of a sensor comprising aworking electrode with a reference electrode wound around thereon.

FIG. 5A illustrates a perspective view of another embodiment of thesensor device; FIG. 5B illustrates an exploded perspective view of theembodiment of FIG. 5A; FIG. 5C illustrates a perspective view of anembodiment of the sensor device that is connected to the sensorelectronics unit via a tether; FIG. 5D illustrates a perspective view ofstill another embodiment of the sensor device that is connected to thesensor electronics unit via a tether; FIG. 5E illustrates a perspectiveview of the embodiment of FIG. 5D disconnected from the sensorelectronics unit; and FIG. 5F illustrates a perspective view of aplurality of sensor devices that are connected to the sensor electronicsunit.

FIG. 6 illustrates a cross-sectional view through one embodiment of thesensor depicting one embodiment of the membrane system.

FIG. 7A illustrates one embodiment of the sensor; FIG. 7B illustratesthe embodiment of FIG. 7A after it has undergone an ablation treatment;FIG. 7C illustrates another embodiment of the sensor; and FIG. 7Dillustrates the embodiment of FIG. 7C after it has undergone an ablationtreatment.

FIG. 8A illustrates one embodiment of the sensor device with a mountingunit comprising a raised upper surface; FIG. 8B illustrates anotherembodiment of the sensor device with a mounting unit comprising a raisedupper surface; FIG. 8C illustrates still another embodiment of thesensor device with a mounting unit comprising a raised upper surface.FIG. 8D illustrates the embodiment of FIG. 8C, after the sensorinsertion process.

FIG. 9A illustrates one embodiment of a user interface displaying ananalyte trend graph, including measured analyte values, estimatedanalyte values, and a zone of clinical risk; and FIG. 9B illustrates oneembodiment of a user interface displaying a gradient bar, includingmeasured analyte values, estimated analyte values, and a zone ofclinical risk.

FIG. 10A is a perspective view of one embodiment of a sensor devicehaving a disposable thin laminate sensor housing; and FIG. 10B is acut-away side cross-sectional view of the embodiment illustrated in FIG.10A.

FIG. 11 illustrates a block diagram associated with one embodiment ofthe sensor electronics unit.

FIG. 12 illustrates one embodiment of a sensor system in which aplurality of sensor devices are grouped together to form a sensor array.

FIGS. 13A and 13B illustrate one embodiment of the sensor device with askin tensioner.

FIGS. 14A, 14B, and 14C illustrate another embodiment of the sensordevice with a skin tensioner.

FIGS. 15A and 15B depict one embodiment of the sensor device thatincorporates Micro Electro Mechanical Systems (MEMS)-based technology.

FIG. 16 illustrates still another embodiment of a sensor device builtbased on MEMS technology.

FIGS. 17A and 17B illustrate still another embodiment of a sensor devicebuilt based on MEMS technology.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples describe in detail some exemplaryembodiments of devices and methods for providing continuous measurementof an analyte concentration. It should be understood that there arenumerous variations and modifications of the devices, systems, andmethods described herein that are encompassed by the present invention.Accordingly, the description of a certain exemplary embodiment shouldnot be deemed to limit the scope of the present invention.

Definitions

In order to facilitate an understanding of the devices and methodsdescribed herein, a number of terms are defined below.

The term “analyte” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a substance or chemical constituent in abiological fluid (for example, blood, interstitial fluid, cerebralspinal fluid, lymph fluid, urine, sweat, saliva, etc.) that can beanalyzed. Analytes can include naturally occurring substances,artificial substances, metabolites, or reaction products. In someembodiments, the analyte for measurement by the sensing regions,devices, and methods is glucose. However, other analytes arecontemplated as well, including, but not limited to:acarboxyprothrombin; acylcarnitine; adenine phosphoribosyl transferase;adenosine deaminase; albumin; alpha-fetoprotein; amino acid profiles(arginine (Krebs cycle), histidine/urocanic acid, homocysteine,phenylalanine/tyrosine, tryptophan); glucagon; ketones (e.g., acetone);ephedrine; terbutaline; O₂; CO₂; potassium; PCO₂; PO₂; sodium,hematocrit; reactive oxygen species; nitric oxide; diols; pyruvatedehydroxgenase; NADPH oxidase; xanthine oxidase; acyl CoA oxidase;plasma amine oxidase; bilirubin; cholesterol; creatinine; gentisic acid;ibuprofen; L-Dopa; methyl Dopa; salicylate; tetracycline; tolazamide;tolbutamide; human chorionic gonadotropin; anesthetic drugs (e.g.,lidocaine); acetyl CoA; intermediaries in the Kreb's cycle (e.g.,citrate, cis-aconitate, D-isocitrate, succinate, fumarate; malate,etc.); anti-seizure drugs (e.g., ACTH, lorazepam, carbamezepine,carnitine, Acetazolamide, Phenytoin sodium, depakote, divalproex sodium,tiagabine hydrochloride, levetiracetam, clonazepam, lamotrigine,nitrazepam, primidone, gabapentin, paraldehyde, phenobarbital,carbamazepine, topiramate, clorazepate dipotassium, carbazepine,diazepam, Ethosuximide, Zonisamide); glutamine; cytochrome oxidase,heparin andrenostenedione; antipyrine; arabinitol enantiomers; arginase;benzoylecgonine (cocaine); biotinidase; biopterin; c-reactive protein;carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid;chloroquine; cholesterol; cholinesterase; conjugated 1-β hydroxy-cholicacid; cortisol; creatine kinase; creatine kinase MM isoenzyme;cyclosporin A; d-penicillamine; de-ethylchloroquine;dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcoholdehydrogenase, alcohol oxidase, alpha 1-antitrypsin, cystic fibrosis,Duchenne/Becker muscular dystrophy, glucose-6-phosphate dehydrogenase,hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E,hemoglobin F, D-Punjab, beta-thalassemia, hepatitis B virus, HCMV,HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD, RNA, PKU,Plasmodium vivax, sexual differentiation, 21-deoxycortisol);desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanusantitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D;fatty acids/acylglycines; triglycerides; free β-human chorionicgonadotropin; free erythrocyte porphyrin; free thyroxine (FT4); freetri-iodothyronine (FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphatedehydrogenase; glutathione; glutathione perioxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I;17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, β);lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (e.g., Immunoglobulin M, Immunoglobulin M, IgG adenovirus,anti-nuclear antibody, anti-zeta antibody, arbovirus, Aujeszky's diseasevirus, dengue virus, Dracunculus medinensis, Echinococcus granulosus,Entamoeba histolytica, enterovirus, Giardia duodenalisa, Helicobacterpylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease),influenza virus, Leishmania donovani, leptospira, measles/mumps/rubella,Mycobacterium leprae, Mycoplasma pneumoniae, Myoglobin, Onchocercavolvulus, parainfluenza virus, Plasmodium falciparum, poliovirus,Pseudomonas aeruginosa, respiratory syncytial virus, rickettsia (scrubtyphus), Schistosoma mansoni, Toxoplasma gondii, Trepenoma pallidium,Trypanosoma cruzi/rangeli, vesicular stomatis virus, Wuchereriabancrofti, yellow fever virus); specific antigens (hepatitis B virus,HIV-1); succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH);thyroxine (T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins, and hormones naturally occurring in blood or interstitialfluids can also constitute analytes in certain embodiments. The analytecan be naturally present in the biological fluid or endogenous, forexample, a metabolic product, a hormone, an antigen, an antibody, andthe like. Alternatively, the analyte can be introduced into the body orexogenous, for example, a contrast agent for imaging, a radioisotope, achemical agent, a fluorocarbon-based synthetic blood, or a drug orpharmaceutical composition, including but not limited to: insulin;ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants(nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons,hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines,methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState, Voranil,Sandrex, Plegine); depressants (barbituates, methaqualone, tranquilizerssuch as Valium, Librium, Miltown, Serax, Equanil, Tranxene);hallucinogens (phencyclidine, lysergic acid, mescaline, peyote,psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine,Percocet, Percodan, Tussionex, Fentanyl, Darvon, Talwin, Lomotil);designer drugs (analogs of fentanyl, meperidine, amphetamines,methamphetamines, and phencyclidine, for example, Ecstasy); anabolicsteroids; and nicotine. The metabolic products of drugs andpharmaceutical compositions are also contemplated analytes. Analytessuch as neurochemicals and other chemicals generated within the body canalso be analyzed, such as, for example, ascorbic acid, uric acid,dopamine, noradrenaline, 3-methoxytyramine (3MT),3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA),5-hydroxytryptamine (5HT), and 5-hydroxyindoleacetic acid (FHIAA).

The phrase “continuously measuring” and like phrases as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to theperiod in which monitoring of analyte concentration is continuously,continually, and or intermittently (but regularly) performed, forexample, about every 5 to 10 minutes.

The term “operably connected” and like terms as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to one ormore components linked to another component(s) in a manner that allowstransmission of signals between the components. For example, one or moreelectrodes can be used to detect the amount of analyte in a sample andconvert that information into a signal; the signal can then betransmitted to a circuit. In this case, the electrode is “operablyconnected” to the electronic circuitry.

The term “host” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to animals (e.g., humans) and plants.

The term “in vivo portion” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the portion of the device(for example, a sensor body, a tissue piercing element, or a sensorunit) adapted for insertion into and/or existence within a living bodyof a host.

The term “ex vivo portion” as used herein is a broad term and is to begiven it ordinary and customary meaning to a person of ordinary skill inthe art (and are not to be limited to a special or customized meaning),and refers without limitation to the portion of the device (for example,a mounting unit) adapted to remain and/or exist outside of a living bodyof a host.

The terms “electrochemically reactive surface”, “electroactive surface”,and like terms as used herein are broad terms, and are to be given theirordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefer without limitation to the surface of an electrode where anelectrochemical reaction takes place. As one example, in a workingelectrode, H₂O₂ (hydrogen peroxide) produced by an enzyme-catalyzedreaction of an analyte being detected reacts and thereby creates ameasurable electric current. For example, in the detection of glucose,glucose oxidase produces H₂O₂ as a byproduct. The H₂O₂ reacts with thesurface of the working electrode to produce two protons (2H⁺), twoelectrons (2e⁻), and one molecule of oxygen (O₂), which produces theelectric current being detected. In the case of the counter electrode, areducible species, for example, O₂ is reduced at the electrode surfacein order to balance the current being generated by the workingelectrode.

The terms “sensing region”, “sensor”, and like terms as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and is not to be limited to aspecial or customized meaning), and refer without limitation to theregion or mechanism of a monitoring device responsible for the detectionof a particular analyte.

The terms “raw data stream” and “data stream” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to ananalog or digital signal directly related to the measured glucoseconcentration from the glucose sensor. In one example, the raw datastream is digital data in “counts” converted by an A/D converter from ananalog signal (for example, voltage or amps) representative of a glucoseconcentration. The terms broadly encompass a plurality of time spaceddata points from a substantially continuous glucose sensor, whichcomprises individual measurements taken at time intervals ranging fromfractions of a second up to, for example, 1, 2, or 5 minutes or longer.

The term “counts” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a unit of measurement of a digital signal.In one example, a raw data stream measured in counts is directly relatedto a voltage (for example, converted by an A/D converter), which isdirectly related to current from the working electrode. In anotherexample, counter electrode voltage measured in counts is directlyrelated to a voltage.

The phrase “distal to” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the spatial relationshipbetween various elements in comparison to a particular point ofreference. For example, some embodiments of a sensor include a membranesystem having a diffusion resistance layer and an enzyme layer. If thesensor is deemed to be the point of reference and the diffusionresistance layer is positioned farther from the sensor than the enzymelayer, then the diffusion resistance layer is more distal to the sensorthan the enzyme layer.

The phrase “proximal to” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the spatial relationshipbetween various elements in comparison to a particular point ofreference. For example, some embodiments of a device include a membranesystem having a diffusion resistance layer and an enzyme layer. If thesensor is deemed to be the point of reference and the enzyme layer ispositioned nearer to the sensor than the diffusion resistance layer,then the enzyme layer is more proximal to the sensor than the diffusionresistance layer.

The terms “membrane system” and “membrane” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to apermeable or semi-permeable membrane that can comprise one or morelayers and constructed of materials, which are permeable to oxygen andmay or may not be permeable to an analyte of interest. In one example,the membrane system comprises an immobilized glucose oxidase enzyme,which enables an electrochemical reaction to occur to measure aconcentration of glucose.

The term “domain” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to regions of a membrane that can be layers,uniform or non-uniform gradients (i.e., anisotropic) or provided asportions of the membrane.

The terms “interferents”, “interfering species”, and like terms as usedherein are broad terms, and are to be given their ordinary and customarymeaning to a person of ordinary skill in the art (and are not to belimited to a special or customized meaning), and refer withoutlimitation to effects or species that interfere with the measurement ofan analyte of interest in a sensor to produce a signal that does notaccurately represent the analyte measurement. In an exemplaryelectrochemical sensor, interfering species can include compounds withan oxidation potential that overlaps with that of the analyte to bemeasured.

Overview

The embodiments described herein provide various mechanisms for directlyinserting a transcutaneous sensor into a host without the use of aseparate applicator or the like, i.e., other than the sensor deviceitself. Direct press insertion of a transcutaneous sensor (e.g., anelectrode) having a wire-like geometry, especially a fine wire, can betechnically challenging because of buckling risks associated with thesensor. Direct press insertion of a sensor also presents challengesrelating to damage during the insertion process to the membrane disposedon the sensor. Without membrane protection, the membrane can be strippedoff from the sensor or be mechanically damaged during the insertionprocess. The embodiments described herein are designed to overcome theaforementioned challenges by providing miniaturized sensor devicescapable of providing structural support (e.g., in the form ofmechanical/structural properties such as column strength) for directinsertion of a transcutaneous sensor and capable of protecting themembrane from damage during the insertion process.

FIG. 1 provides a schematic side view of an exemplary embodiment of atranscutaneous sensor device 100 configured to continuously measureanalyte concentration (e.g., glucose concentration) in a host to providea data stream representative of the host's analyte concentration. In theparticular embodiment illustrated in FIG. 1, the sensor device 100comprises an in vivo portion 160 (also referred to as a sensor unit)configured for insertion under the skin of the host and an ex vivoportion 170 configured to remain above the host's skin surface aftersensor insertion. The in vivo portion 160 comprises a tissue piercingelement 110 configured for piercing the skin 180 of the host and asensor body 120 comprising a support member 130 that is comprised of oneor more electrodes and a membrane 140 disposed over at least a portionof the support member 130. The ex vivo portion 170 comprises a mountingunit 150 that may comprise a sensor electronics unit embedded ordetachably attached therein, or alternatively may be configured tooperably connect to a separate sensor electronics unit.

In some embodiments, the sensor device may be substantially modular andformed of multiple separate components (e.g., the tissue piercingelement, the sensor body, the mounting unit, the sensor electronicsunit) that are detachable from each other. In these embodiments,pressure-resistant bonds may be formed between the different componentsby welding, soldering, or use of adhesives to join the different pieces.In other embodiments, two or more components of the sensor device may beformed as one piece. For example, the tissue piercing element and thesensor body may be fabricated as a single unitary piece. The differentcomponents of the transcutaneous sensor device will now be described ingreater detail.

Tissue Piercing Element

The tissue piercing element 110 of the sensor device 100 is configuredto pierce the skin 180 of the host and to open and define a passage forinsertion of the sensor body 120 into a tissue of the host. The skingenerally comprises multiple layers, including the epidermis, dermis,and subcutaneous layers. The epidermis comprises a number of layerswithin its structure including the stratum corneum, which is theoutermost layer and is generally from about 10 to 20 microns thick, andthe stratum germinativum, which is the deepest layer of the epidermis.While the epidermis generally does not contain blood vessels, itexchanges metabolites by diffusion to and from the dermis. While notwishing to be bound by theory, it is believed that because the stratumgerminativum is supported by vascularization for survival, theinterstitial fluid at the stratum germinativum sufficiently represents ahost's analyte (e.g., glucose) levels. Beneath the epidermis is thedermis, which is from about 1 mm to about 3 mm thick and contains bloodvessels, lymphatics, and nerves. The subcutaneous layer lies underneaththe dermis and is mostly comprised of fat. The subcutaneous layer servesto insulate the body from temperature extremes. It also containsconnective tissue and a small amount of blood vessels.

In some embodiments, the in vivo portion 160 of the sensor device 100may have a length long enough to allow for at least a portion of thesensor body 120 to reside within the stratum germinativum. This may bedesirable in some instances because the epidermis does not contain asubstantial number of blood vessels or nerve endings; thus, sensorinsertion may be relatively painless, and the host may not experiencemuch bleeding or discomfort from the insertion. In some of theseembodiments, the in vivo portion 160 of the sensor device 100 can have alength of from about 0.1 mm to about 1.5 mm, or from about 0.2 mm toabout 0.5 mm. In other embodiments, the in vivo portion 160 of thesensor device 100 may have a length that allows for at least a portionof the sensor body 120 to reside in the dermis layer. This may bedesirable in some instances because the dermis is well vascularized, ascompared to the subcutaneous layer, and thus can provide sufficientanalytes (e.g., glucose) for measurement and reduce measurement lagsassociated with changes of analyte concentrations of a host, such asthose that occur after meals. The metabolically active tissue near theouter dermis (and also the stratum germinativum) provides rapidequilibrium of the interstitial fluid with blood. In some of theseembodiments, the in vivo portion 160 of the sensor device can have alength of from about 1 mm to about 7 mm, or from about 2 mm to about 6mm. In still other embodiments, the in vivo portion 160 of the sensordevice 100 may have a length that allows for at least a portion of thesensor body 120 to reside in the subcutaneous layer. While not wishingto be bound by theory, it is believed that because the subcutaneouslayer serves to insulate the body from temperature extremes, thesubcutaneous layer may reduce variations of analyte concentrationreadings associated with temperature fluctuations. In some of theseembodiments, the in vivo portion 160 of the sensor device can have alength of from about 3 mm to about 10 mm, or from about 5 mm to about 7mm.

The tissue piercing element may have any of a variety of geometricshapes and dimensions, including ones that minimize tissue trauma andreduce the force required for skin penetration. For example, in someembodiments, the tissue piercing element may comprise a substantiallyconically-shaped distal tip, as illustrated in FIGS. 1 and 2A, such thatthe cross-sectional dimensions (e.g., diameter) of the tissue piercingelement tapers to a point 118 at the distal end of the tip, therebyproviding a sharpened leading edge configured to facilitate skinpenetration. As illustrated in FIG. 2B, in other embodiments, the distaltip of the tissue piercing element may be beveled with a bevel angle α,such as, for example, an angle of from about 5° to about 66°, or fromabout 10° to about 55°, or from about 40° to about 50°. In furtherembodiments, one or more surfaces of the tip may be curved, such asillustrated in FIGS. 2C, 2D, 2E, 2F, 2G, 2H, and 3D, so as to facilitateskin penetration when the sensor device is pushed downwards. In someembodiments, a curved surface may be advantageous because it providesthe tissue piercing element with a greater cutting surface area than astraight surface, and thus provide a smoother and more controlledinsertion of the sensor unit through the skin. Also, a tissue piercingelement with a curved surface can or cause less trauma to the piercedtissue than one with a straight surface.

The tissue piercing element of the sensor device is designed to haveappropriate flexibility and hardness and sufficient column strength toallow it to remain intact and to prevent it from substantial bucklingduring insertion of the in vivo portion of the sensor device through theskin of the host. Any of a variety of biocompatible materials havingthese characteristics may be used to form the tissue piercing element,including, but not limited to, metals, ceramics, semiconductors,organics, polymers, composites, and combinations or mixtures thereof.Metals that may be used include stainless steel (e.g., 18-8 surgicalsteel), nitinol, gold, silver, nickel, titanium, tantalum, palladium,gold, and combinations or alloys thereof, for example. Polymers that maybe used include polycarbonate, polymethacrylic acid, ethylenevinylacetate, polytetrafluorethylene (TEFLON®), and polyesters, for example.In some embodiments, the tissue piercing element may serve as areference electrode and comprise a conductive material, such as asilver-containing material, for example. In certain embodiments, thetissue piercing element has sufficient column strength to allow the userto press the sensor unit through the skin using the force from a thumbor finger, without substantial buckling of the tissue piercing element.Accordingly, the structure of the tissue piercing unit does not failwhen it is subjected to resistance (e.g., axial force) associated withthe penetration of tissue and skin. In some embodiments, the tissuepiercing element may have a column strength capable of withstanding anaxial load greater than about 0.5 Newtons, or greater than about 1Newton, or greater than about 2 Newtons, or greater than about 5Newtons, or greater than about 10 Newtons, without substantial buckling.Often, an increase in the column thickness of an object will alsoincrease its column strength. In some embodiments, the base 116 of thedistal tip may have an outside diameter of from about 0.05 mm to about 1mm, or from about 0.1 mm to about 0.5 mm, or from about 0.15 mm to about0.3 mm, to provide the desired column strength for the tissue piercingelement.

Some of the tissue piercing elements described herein are configured toprotect the membrane of the sensor body. As described elsewhere herein,the membrane may be relatively delicate and thus may be damaged duringinsertion of the sensor unit into the host. Consequently, any damagesustained by the membrane can affect the sensor device's performance andits ability to function properly. As illustrated in FIG. 1, in someembodiments, one or more portions of the tissue piercing element 110 isformed with a cross-sectional area (along a plane transverse to thelongitudinal axis of the tissue piercing element 110) larger than thatof the sensor body 120. By having a cross-sectional area larger thanthat of the sensor body 120, the tissue piercing element 110 of thesensor device 100 is configured to pierce the skin 180 of the host andto open and define a passage for insertion of the sensor body 120 intothe tissue. Thus, the risk of a penetration resistance force damagingand/or stripping the membrane 140 off from the rest of the sensor body120 during the insertion process is minimized. In some embodiments, thelargest dimension of the cross section transverse to a longitudinal axisof the tissue piercing element is less than about 0.1 mm, or less thanabout 0.05 mm, or less than about 0.03 mm.

In some embodiments, one or more layers of one or more polymers and/orbioactive agents, as described elsewhere herein, can be coated onto thetissue piercing element. The use of bioactive agents to coat the surfaceof the tissue piercing element can provide a release of bioactive agentsin the subcutaneous tissue during and/or after insertion of the in vivoportion of the sensor device. In further embodiments, one or morepolymer layers can be used to control the release rate of the one ormore bioactive agents. Such polymers can include, but are not limitedto, parylene, parylene C, parylene N, parylene F,poly(hydroxymethyl-p-xylylene-co-p-xylylene) (PHPX),poly(lactic-co-glycolic acid) (PLGA), polyethylene-co-vinyl acetate(PEVA), Poly-L-lactic acid (PLA), poly N-butyl methacrylate (PBMA),phosphorylcholine, poly(isobutylene-co-styrene), polyoxyethylene (POE),polyglycolide (PGA), (poly(L-lactic acid), poly(amic acid) (PAA,polyethylene glycol (PEG), derivatives of one or more of these polymers,and combinations or mixtures thereof.

In some embodiments, one or more regions of the surface of the tissuepiercing element may comprise one or more recessed portions (e.g.,cavities, indentations, openings, grooves, channels, etc.) configured toserve as reservoirs or depots for holding bioactive agents. The recessedportions may be formed at any preselected location and have anypreselected depth, size, geometrical configuration, and dimensions, inaccordance with the intended application. Use of reservoirs or depotscan increase the amount of bioactive agents the tissue piercing elementis capable of carrying and delivering. In further embodiments, thetissue piercing element may be hollow with a cavity and connected viavarious passages with one or more openings on its surface, so thatbioactive agents can be released from the cavity via the openings. Insome embodiments, for example as shown FIGS. 3A and 3B, the tissuepiercing element 310 comprises a pocket 312 shaped and dimensioned tosupport a sensor 314 with a membrane disposed thereon.

In certain embodiments, the in vivo portion of the sensor device isconfigured to remain substantially stationary within the tissue of thehost, so that migration or motion of the sensor body with respect to thesurrounding tissue is minimized. Migration or motion can causeinflammation at the sensor implant site due to irritation, and can alsocause noise on the sensor signal due to motion-related artifact.Therefore, it can be advantageous to provide an anchoring mechanism thatprovides support for the in vivo portion of the sensor device to avoidthe aforementioned problems. In some embodiments, the tissue piercingelement may comprise a surface with one or more regions that aretextured. Texturing may roughen the surface of the tissue piercingelement and thereby provide a surface contour with a greater surfacearea than that of a non-textured (e.g., smooth) surface. Accordingly,the amount of bioactive agents, polymers, and/or coatings that thetissue piercing element can carry and be released in situ is increased,as compared to that with a non-textured surface. Furthermore, it isbelieved that a textured surface may also be advantageous in someinstances, because the increased surface area may enhance immobilizationof the in vivo portion of the sensor device within the tissue of thehost. In certain embodiments, the tissue piercing element may comprise asurface topography with a porous surface (e.g. porous parylene), ridgedsurface, or the like. In certain embodiments, the anchoring can beprovided by prongs, spines, barbs, wings, hooks, a bulbous portion (forexample, at the distal end), an S-bend along the tissue piercingelement, a gradually changing diameter, combinations thereof, or thelike, which can be used alone or in combination to stabilize the sensorwithin the subcutaneous tissue. For example, in certain embodiments, thetissue piercing element may comprise one or more anchoring membersconfigured to splay outwardly (e.g., in a direction toward a planeperpendicular to the longitudinal axis of the sensor unit) during orafter insertion of the sensor unit. Outward deployment of the anchoringmember facilitates anchoring of the sensor unit, as it results in thetissue piercing element pressing against the surrounding tissue and thusreduces (or prevents) movement and/or rotation of the sensor unit. Insome embodiments, the anchoring members are formed of a shape memorymaterial, such as nitinol, which can be configured to transform from amartensitic state to an austenitic state at a specific temperature(e.g., room temperature or body temperature). In the martensitic state,the anchoring members are ductile and in a contracted configuration. Inthe austenitic state, the anchoring members deploy to form a largerpredetermined shape while becoming more rigid. While nitinol isdescribed herein as an example of a shape memory material that may bechosen to form the anchoring member, it should be understood that otherlike materials (e.g., shape memory material) may also be used.

The tissue piercing element of the sensor device may be introducedsubcutaneously at any of a variety of angles with respect to themounting surface, i.e., the bottom surface of the mounting unit, andthus the skin surface. For example, in some embodiments, the distal tipof the tissue piercing element may extend substantially perpendicular tothe mounting surface, but in other embodiments, the distal tip mayextend at an angle with respect to the mounting surface of about 15°,20°, 30°, 40°, 45°, 60°, 75°, 80°, 90°, 105°, 100°, 120°, 135°, 140°,150°, 160°, or 165° degrees, for example.

In alternative embodiments, to provide protection of the membrane duringinsertion of the sensor device, the sensor body may be embedded orencapsulated in a needle formed of a biodegradable material. Followinginsertion, the needle gradually biodegrades, leaving behind the sensorbody which can then be activated. Any of a variety of biodegradablematerials (e.g., a non-interfering carbohydrate) can be used. In someembodiments, the biodegradable material may include a certainconcentration of an analyte to be measured, so that an initialcalibration point of the sensor device can be provided.

Sensor Body

Referring back to the embodiment of FIG. 1, in one embodiment, thesensor device 100 comprises a sensor body 120 that includes one or moreelectrodes configured to continuously measure blood analyteconcentrations in a host. The sensor body 120 may also include areference electrode (and/or a counter electrode) against which theworking electrode may be referenced. Alternatively or additionally, thetissue piercing element 110 may also be employed as a referenceelectrode. The working electrode may comprise a conductive material,such as, for example, platinum, platinum-iridium, gold, palladium,iridium, graphite, carbon, a conductive polymer, an alloy, and/or thelike, suitable to provide electroactive surfaces. The referenceelectrode may comprise a conductive material, such as asilver-containing material, for example. A membrane, as described ingreater detail elsewhere herein, is disposed over at least a portion ofthe electrodes.

As described elsewhere herein, the membrane 140 of the sensor body 120,if not protected, can become damaged during insertion, which in turn canaffect the sensor device's performance and its ability to functionproperly. FIG. 1 illustrates one embodiment that is configured toprovide protection of the membrane 140. In this particular embodiment,the sensor body 120 includes a support member 130 that extends from theproximal end of the tissue engaging element 110 to the mounting unit150. The support member 130 can be comprised of both a working electrodeand a reference electrode. In an alternative embodiment, as illustratedin FIG. 4, the support member 430 comprises the working electrode 422,and a separate reference electrode 424 is helically wound around theworking electrode 422. A mounting unit 450 is provided with an adhesivematerial or adhesive layer 454 (e.g., an adhesive pad) disposed on themounting unit's 450 lower surface and may also include a releasablebacking layer. A membrane 414 is disposed on the working electrode 422and the reference electrode 424. In this alternative embodiment, thehelical winding arrangement of the reference electrode 424 may provideadditional column strength to at least a portion of the support member430 and ensure that the support member 430 projects at a preselectedangle with respect to the mounting surface. In still another alternativeembodiment, the support member may not comprise any electrode. Instead,a working electrode (and optionally a reference electrode) may beconfigured to encircle, encompass, helically wind around, or otherwiselie substantially juxtapositioned to the support member. An insulatorcan be provided between the support member (if conductive), the workingelectrode, and the reference electrode, to provide electricalinsulation.

In alternative embodiments, the sensor device may comprise two or moresensor bodies. For example, one sensor body may be associated with theworking electrode and another sensor body may be associated with thereference electrode. The plurality of sensor bodies may be joined to asingle tissue piercing element, or alternatively, formed as independentstructures, i.e., with each sensor body being associated with adifferent tissue piercing element. In embodiments wherein the pluralityof sensor bodies are formed as independent structures, the individualsensor bodies may be inserted in proximal, but separate, locations. Withthis arrangement, the separation of the working and reference electrodesmay provide electrochemical stability.

The support member may be formed of any of a variety of biocompatiblematerials capable of providing appropriate flexibility and hardness andsufficient column strength, such that the support member can be pushedthrough the skin of the host without substantial buckling. In certainembodiments, the support member has sufficient column strength to allowthe user to press the sensor unit through the skin using the force froma thumb or finger, without substantial buckling of the support member.Accordingly, the structure of the support member does not fail when itis subjected to resistance (e.g., axial force) associated with thepenetration of tissue and skin. Materials that may be used to form thesupport member include, but are not limited to, stainless steel,titanium, tantalum, platinum, platinum-iridium, iridium, certainpolymers, and/or the like. In certain embodiments, the support membermay have a column strength capable of withstanding an axial load greaterthan about 0.5 Newtons, or greater than about 1 Newton, or greater thanabout 1.5 Newtons, or greater than about 2 Newtons, or greater thanabout 5 Newtons, or greater than about 10 Newtons, without substantialbuckling.

While the support members 130, 430 illustrated in FIGS. 1 and 4 areformed with a circular cross section, in other embodiments the crosssection of the support member may have any of a variety ofcross-sectional shapes, such as oval, square, rectangular, triangular,polyhedral, star-shaped, C-shaped, T-shaped, X-shaped, Y-Shaped,irregular, or the like, for example. In certain embodiments, the supportmember may be formed of a conductive core (e.g., a conductive wire)covered by one or more conducting layers (and may include interveninginsulating layers provided for electrical isolation). The conductivelayers can be comprised of any suitable material; however, in certainembodiments and depending upon the fabrication methods, it can bedesirable to employ a conductive layer comprising conductive particles(i.e., particles of a conductive material) in a polymer or other binder.

Similar to the tissue piercing element, some of the support membersdescribed herein may comprise one or more recessed portions (e.g.,cavities, indentations, openings, grooves, channels, etc.) configured toserve as reservoirs or depots for holding bioactive agents. The recessedportions may be formed at any preselected location and have anypreselected depth, size, geometrical configuration, and dimensions, inaccordance with the intended application. Use of reservoirs or depotscan increase the amount of bioactive agents the support member iscapable of carrying and delivering. In further embodiments, the supportmember may be hollow with a cavity and formed with one or more openingson its surface, so that bioactive agents can be released from the cavityvia the openings.

Similar to the tissue piercing element, some of the support membersdescribed herein may comprise a surface with one or more regions thatare textured to provide a surface contour with a greater surface areathan that of a non-textured (e.g., smooth) surface. In certainembodiments, the support member may comprise a surface topography with aporous surface (e.g. porous parylene), ridged surface, or the like.Additionally or alternatively, the support member can be provided withprongs, spines, barbs, wings, hooks, a bulbous portion (for example, atthe distal end), an S-bend along the tissue piercing element, agradually changing diameter, combinations thereof, or the like, whichcan be used alone or in combination to stabilize the sensor within thesubcutaneous tissue.

In certain embodiments, a membrane is disposed over at least a portionof the support member and the sensor. As illustrated in the FIG. 1, insome embodiments, the sensor body 120 is configured to have a smallercross-sectional area than that of the tissue piercing element 110, suchthat the membrane 140 of the sensor body 120 does not project radiallybeyond the largest perimeter (e.g., circumference) of the tissuepiercing element 110. Thus, the membrane 140 is protected duringinsertion of the in vivo portion 160 of the sensor device 100. In someembodiments, the largest dimension of the cross section transverse to alongitudinal axis of the sensor body 120 is less than about 0.05 mm, orless than about 0.04 mm, or less than about 0.025 mm.

While FIG. 1 illustrates one configuration for providing membraneprotection, other sensor body configurations may also be used. Forexample, some of the sensor bodies described herein may include asupport member 330 configured to partially surround a sensor, asillustrated in FIGS. 3A and 3B, or configured to substantially surrounda sensor, as illustrated in FIG. 3C. Unlike other embodiments describedelsewhere herein, in the embodiments illustrated in FIGS. 3A, 3B, and3C, the support member 330 does not comprise a working electrode.Rather, one or more working electrodes are arranged as pieces distinctfrom the support member 330. In some embodiments, the support member 330may also serve as a reference electrode.

In the embodiment illustrated in FIG. 3A, the support member 330comprises a longitudinal recess 332 configured to at least partiallyaccommodate a sensor (e.g., a working electrode with a membrane disposedthereon). In some embodiments, the longitudinal recess may have a lengthcorresponding to less than about 90% of the length of the support member330, or less than about 75%, or less than about 50%, or less than about33%, or less than about 25%. In other embodiments, the longitudinalrecess may extend substantially across the entire length of the supportmember 330, as illustrated in FIG. 3B. In certain embodiments, thesupport member 330 may surround more than about 10% of the outerperimeter (e.g., circumference) of the sensor, or more than about 25%,or more than about 33%, or more than about 50%, or more than about 75%.

As illustrated in FIG. 3C, in some embodiments wherein the sensor (e.g.,the working electrode) is substantially surrounded by the support member330, the support member 330 may be provided with one or more windowportions 334 (i.e., openings or slots extending through the wallthickness of the support member 330) that exposes certain portions ofthe electrode to biological fluid (e.g., interstitial fluid) and thusallow biological fluid to diffuse toward and contact the workingelectrode's electroactive surface and the membrane disposed thereon. Inthis embodiment, the working electrode and the membrane disposed thereonare essentially housed within the support member 330 and are thusprotected during packing, handling, and/or insertion of the device. Thewindow portions 334 may have any of a variety of shapes and dimensions.For example, in some embodiments, the window portions may be formed tohave a circular or substantially circular shape, but in otherembodiments, the electrode may be formed with a shape resembling anellipse, a polygon (e.g., triangle, square, rectangle, parallelogram,trapezoid, pentagon, hexagon, octagon), or the like. In certainembodiments, the windows portions may comprise sections that extendaround the perimeter of the longitudinal cross section of the supportmember. For example, the support member may be made by using a hypo-tubewith window portions cut out in a spiral configuration, by ablation,etching, or other like techniques.

FIG. 5A is a perspective view of one embodiment of a sensor device 500with wires 552, 554 extending therefrom for connecting electrodes 522,524 with the sensor electronics unit. FIG. 5B is an exploded perspectiveview of the embodiment illustrated in FIG. 5A, showing the tissuepiercing element 510 and the support member 530 formed as a unitarypiece as a sensor unit formed of a conductive material. The sensor bodyin this embodiment comprises the working electrode 522 and the referenceelectrode 524. A first insulator 556 is provided for electricallyinsulating the head 516 of the sensor unit 514 from the referenceelectrode 524. The reference electrode 524 is associated with a wire 554for connecting the reference electrode 524 to the sensor electronicsunit 590. A second insulator 557 is provided that is configured to bedisposed between the support member 530 and the reference electrode 524to provide electrical insulation therebetween. A third insulator 558 isprovided for electrically insulating the reference electrode 524 fromthe working electrode 522, which is located most distal from the sensorunit head 516 in this particular embodiment. Because the support member530 is formed of a conductive material, it provides an electricalconnection between the working electrode 522 and the sensor unit head516, which is connected to the sensor electronics unit 590 via a wire552.

As shown in FIG. 5C, in some embodiments, the sensor device 500 maycomprise a plurality of sensor units 522, 524 brought together by amounting unit 550. In further embodiments, the plurality of sensor unitsmay include a first sensor unit associated with a working electrode anda second sensor unit associated with a reference electrode.Alternatively, both the first and second sensor units may each comprisea working and reference electrode.

Any of a variety of electrodes can be employed for the sensor device.For example, referring back to FIG. 4, in one embodiment, the supportmember 430 may comprise a working electrode comprising an electroactivesurface portion 422 and a separate reference electrode 424 helicallywound around the working electrode. In this particular embodiment, aninsulator 426 is disposed between the working electrode (i.e., thesupport member 430) and the reference electrode 424, to provideelectrical insulation therebetween. In should be understood that in someembodiments, the electrodes may form the support member of the sensorbody, in part or in whole, but in other embodiments, the electrodes maybe elements that are distinct from the support member.

FIG. 7A illustrates one embodiment of an electrode comprising aconductive core 710, a first layer 720 that at least partially surroundsthe core 710, a second layer 730 that at least partially surrounds thefirst layer 720, and a third layer 740 that at least partially surroundsthe second layer 730. These layers, which collectively form an elongatedbody, can be deposited onto the conductive core by any of a variety oftechniques, such as, for example, by employing dip coating, plating,extrusion, or spray coating processes. In some embodiments, the firstlayer 720 can comprise a conductive material, such as, for example,platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon,a conductive polymer, an alloy, and/or the like, configured to providesuitable electroactive surfaces for one or more working electrodes. Incertain embodiments, the second layer 730 can correspond to an insulatorand comprise an insulating material, such as a non-conductive (e.g.,dielectric) polymer (e.g., polyurethane, polyimide, or parylene). Insome embodiments, the third layer 740 can correspond to a referenceelectrode and comprise a conductive material, such as, asilver-containing material, including, but not limited to, apolymer-based conducting mixture. FIG. 7B illustrates one embodiment ofthe electrode of FIG. 7A, after it has undergone laser ablationtreatment. As shown, a window region 722 is formed when the ablationremoves the second and third layers 730, 740, to expose an electroactivesurface of the first conductive layer 720, wherein the exposedelectroactive surface of the first conductive layer 720 correspond to aworking electrode.

FIG. 7C illustrates another embodiment of an electrode. In thisembodiment, in addition to an conductive core 710, a first layer 720, asecond layer 730, and a third layer 740, the electrode further comprisesa fourth layer 750 and a fifth layer 770. In a further embodiment, thefirst layer 720 and the second layer 730 can be formed of a conductivematerial and an insulating material, respectively, similar to thosedescribed in the embodiment of FIG. 7A. However, in this particularembodiment, the third layer 740 can be configured to provide the sensorwith a second working electrode, in addition to the first workingelectrode provided by the first layer 720. In this particularembodiment, the fourth layer 750 can comprise an insulating material andprovide insulation between the third layer 740 and the fifth layer 760,which can correspond to a reference electrode and comprise theaforementioned silver-containing material. It is contemplated that othersimilar embodiments are possible. For example, in alternativeembodiments, the electrode can have 6, 7, 8, 9, 10, or more layers, eachof which can be formed of conductive or non-conductive material. FIG. 7Dillustrates one embodiment of the electrode of FIG. 7C, after it hasundergone laser ablation treatment. Here, two window regions, a firstwindow region 722 and a second window region 742, are formed, with eachwindow region having a different depth and corresponding to a workingelectrode distinct from the other.

Membrane System

The membrane systems described herein can be utilized with any of thesensors (e.g., electrodes) described elsewhere herein for measuringanalyte levels in a biological fluid, such as sensors for monitoringglucose levels for individuals having diabetes. In some embodiments, theanalyte-measuring sensor is a continuous sensor. Although some of thedescription that follows is directed at glucose-measuring devices, themembrane systems described herein are not limited to use in devices thatmeasure or monitor glucose. Rather, these membrane systems are suitablefor use in any of a variety of devices, including, for example, devicesthat detect and quantify other analytes present in biological fluids(e.g., cholesterol, amino acids, alcohol, galactose, and lactate).

It should be understood that any of the layers described herein, e.g.,the electrode, interference, enzyme, or diffusion resistance layer, maybe omitted. In addition, it should be understood the membrane system canhave any of a variety of layer arrangements, with some arrangementshaving more or less layers than other arrangements. For example, in someembodiments, the membrane system can comprise one interference layer,one enzyme layer, and two diffusion resistance layers, but in otherembodiments, the membrane system can comprise one electrode layer, oneenzyme layer, and one diffusion resistance layer.

In some embodiments, one or more layers of the membrane system can beformed from materials such as silicone, polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutyleneterephthalate (PBT), polymethylmethacrylate (PMMA), polyether etherketone (PEEK), polyamides, polyimides, polystyrenes, polyurethanes,cellulosic polymers, poly(ethylene oxide), poly(propylene oxide) andcopolymers and blends thereof, polysulfones and block copolymers thereofincluding, for example, di-block, tri-block, alternating, random andgraft copolymers.

In some embodiments, one or more layers of the membrane system areformed from a silicone polymer. In further embodiments, the siliconecomposition can have molecular weight of from about 50,000 to about800,000 g/mol. It has been found that having the polymers formed withthis molecular weight range facilitates the preparation of cross-linkedmembranes that provide the strength, tear resistance, stability, andtoughness advantageous for use in vivo.

In some embodiments, the silicone polymer is a liquid silicone rubberthat may be vulcanized using a metal—(e.g., platinum), peroxide-, heat-,ultraviolet-, or other radiation-catalyzed process. In some embodiments,the silicone polymer is a dimethyl- and methylhydrogen-siloxanecopolymer. In some embodiments, the copolymer has vinyl substituents. Insome embodiments, commercially available silicone polymers can be used.For example, commercially available silicone polymer precursorcompositions can be used to prepare the blends, such as described below.In one embodiment, MED-4840 available from NUSIL® Technology LLC is usedas a precursor to the silicone polymer used in the blend. MED-4840consists of a 2-part silicone elastomer precursor includingvinyl-functionalized dimethyl- and methylhydrogen-siloxane copolymers,amorphous silica, a platinum catalyst, a crosslinker, and an inhibitor.The two components can be mixed together and heated to initiatevulcanization, thereby forming an elastomeric solid material. Othersuitable silicone polymer precursor systems include, but are not limitedto, MED-2174 peroxide-cured liquid silicone rubber available from NUSIL®Technology LLC, SILASTIC® MDX4-4210 platinum-cured biomedical gradeelastomer available from DOW CORNING®, and Implant Grade Liquid SiliconePolymer (durometers 10-50) available from Applied Silicone Corporation.

In some embodiments, one or more layer of the membrane system is formedfrom a blend of a silicone polymer and a hydrophilic polymer. By“hydrophilic polymer”, it is meant that the polymer has a substantiallyhydrophilic domain in which aqueous substances can easily dissolve. Ithas been found that use of such a blend may provide high oxygensolubility and allow for the transport of glucose or other suchwater-soluble molecules (for example, drugs) through the membrane. Inone embodiment, the hydrophilic polymer comprises both a hydrophilicdomain and a partially hydrophobic domain (e.g., a copolymer), wherebythe partially hydrophobic domain facilitates the blending of thehydrophilic polymer with the hydrophobic silicone polymer. In oneembodiment, the hydrophobic domain is itself a polymer (i.e., apolymeric hydrophobic domain). For example, in one embodiment, thehydrophobic domain is not a simple molecular head group but is ratherpolymeric.

The silicone polymer for use in the silicone/hydrophilic polymer blendcan be any suitable silicone polymer, include those described above. Thehydrophilic polymer for use in the silicone/hydrophilic polymer blendcan be any suitable hydrophilic polymer, including but not limited tocomponents such as polyvinylpyrrolidone (PVP), polyhydroxyethylmethacrylate, polyvinylalcohol, polyacrylic acid, polyethers such aspolyethylene glycol or polypropylene oxide, and copolymers thereof,including, for example, di-block, tri-block, alternating, random, comb,star, dendritic, and graft copolymers (block copolymers are discussed inU.S. Pat. Nos. 4,803,243 and 4,686,044). In one embodiment, thehydrophilic polymer is a copolymer of poly(ethylene oxide) (PEO) andpoly(propylene oxide) (PPO), such as PEO-PPO diblock copolymers,PPO-PEO-PPO triblock copolymers, PEO-PPO-PEO triblock copolymers,alternating block copolymers of PEO-PPO, random copolymers of ethyleneoxide and propylene oxide, and blends thereof, for example. In someembodiments, the copolymers can be optionally substituted with hydroxysubstituents. Commercially available examples of PEO and PPO copolymersinclude the PLURONIC® brand of polymers available from BASF®. SomePLURONIC® polymers are triblock copolymers of poly(ethyleneoxide)-poly(propylene oxide)-poly(ethylene oxide) having the generalmolecular structure:HO—(CH₂CH₂O)_(x)—(CH₂CH₂CH₂O)_(y)—(CH₂CH₂O)_(x)—OHwherein the repeat units x and y vary among various PLURONIC® products.The poly(ethylene oxide) blocks act as a hydrophilic domain allowing thedissolution of aqueous agents in the polymer. The poly(propylene oxide)block acts as a hydrophobic domain facilitating the blending of thePLURONIC® polymer with a silicone polymer. In one embodiment, PLURONIC®F-127 is used having x of approximately 100 and y of approximately 65.The molecular weight of PLURONIC® F-127 is approximately 12,600 g/mol asreported by the manufacture. Other PLURONIC® polymers includePPO-PEO-PPO triblock copolymers (e.g., PLURONIC® R products). Othersuitable commercial polymers include, but are not limited to,SYNPERONICS® products available from UNIQEMA®.

The membrane system of some embodiments can comprise at least onepolymer containing a surface-active group. The term “surface-activegroup” and “surface-active end group” as used herein are broad terms andare used in their ordinary sense, including, without limitation,surface-active oligomers or other surface-active moieties havingsurface-active properties, such as alkyl groups, which are inclined tomigrate towards a surface of a membrane formed thereof. In someembodiments, the surface-active group-containing polymer is asurface-active end group-containing polymer. In some of theseembodiments, the surface-active end group-containing polymer is apolymer having covalently bonded surface-active end groups. However, itis contemplated that other surface-active group-containing polymers mayalso be used and can be formed by modification of fully-reacted basepolymers via the grafting of side chain structures, surface treatmentsor coatings applied after membrane fabrication (e.g., viasurface-modifying additives), blending of a surface-modifying additiveto a base polymer before membrane fabrication, immobilization of thesurface-active-group-containing soft segments by physical entrainmentduring synthesis, or the like.

Base polymers useful for certain embodiments can include any linear orbranched polymer on the backbone structure of the polymer. Suitable basepolymers can include, but are not limited to, epoxies, polyolefins,polysiloxanes, polyethers, acrylics, polyesters, carbonates, andpolyurethanes, wherein polyurethanes can include polyurethane copolymerssuch as polyether-urethane-urea, polycarbonate-urethane,polyether-urethane, silicone-polyether-urethane,silicone-polycarbonate-urethane, polyester-urethane, and the like. Insome embodiments, base polymers can be selected for their bulkproperties, such as, but not limited to, tensile strength, flex life,modulus, and the like. For example, polyurethanes are known to berelatively strong and to provide numerous reactive pathways, whichproperties may be advantageous as bulk properties for a membrane layerof the continuous sensor.

In some embodiments, a base polymer synthesized to have hydrophilicsegments can be used to form at least a portion of the membrane system.For example, a linear base polymer including biocompatible segmentedblock polyurethane copolymers comprising hard and soft segments can beused. It is contemplated that polyisocyanates can be used for thepreparation of the hard segments of the copolymer and may be aromatic oraliphatic diisocyanates. The soft segments used in the preparation ofthe polyurethane can be derived from a polyfunctional aliphatic polyol,a polyfunctional aliphatic or aromatic amine, or the like that can beuseful for creating permeability of the analyte (e.g., glucose)therethrough, and can include, for example, polyvinyl acetate (PVA),poly(ethylene glycol) (PEG), polyacrylamide, acetates, polyethyleneoxide (PEO), polyethylacrylate (PEA), polyvinylpyrrolidone (PVP), andvariations thereof (e.g., PVP vinyl acetate).

Alternatively, in some embodiments, the membrane system can comprise acombination of a base polymer (e.g., polyurethane) and one or morehydrophilic polymers, such as, PVA, PEG, polyacrylamide, acetates, PEO,PEA, PVP, and variations thereof (e.g., PVP vinyl acetate), as aphysical blend or admixture, wherein each polymer maintains its uniquechemical nature. It is contemplated that any of a variety of combinationof polymers can be used to yield a blend with desired glucose, oxygen,and interference permeability properties. For example, in someembodiments, the membrane can comprise a mixture or blend of apolycarbonate-urethane base polymer and PVP, but in other embodiments, ablend of a polyurethane, or another base polymer, and one or morehydrophilic polymers can be used instead. In some of the embodimentsinvolving use of PVP, the PVP portion of the polymer blend can comprisefrom about 5% to about 50% by weight of the polymer blend, or from about15% to 20%, or from about 25% to 40%. It is contemplated that PVP ofvarious molecular weights may be used. For example, in some embodiments,the molecular weight of the PVP used can be from about 25,000 daltons toabout 5,000,000 daltons, or from about 50,000 daltons to about 2,000,000daltons, or from 6,000,000 daltons to about 10,000,000 daltons.

Coating solutions that include at least two surface-activegroup-containing polymers can be made using any of the methods offorming polymer blends known in the art. In one exemplary embodiment, asolution of a polyurethane containing silicone end groups is mixed witha solution of a polyurethane containing fluorine end groups (e.g.,wherein the solutions include the polymer dissolved in a suitablesolvent such as acetone, ethyl alcohol, DMAC, THF, 2-butanone, and thelike). The mixture can then be coated onto to the surface of theelongated conductive body using the coating process described elsewhereherein. The coating can then be cured under high temperature (e.g.,about 50-150° C.), as the elongated conductive body is advanced throughthe curing station.

Some amount of cross-linking agent can also be included in the mixtureto induce cross-linking between polymer molecules. Non-limiting examplesof suitable cross-linking agents include isocyanate, carbodiimide,gluteraldehyde or other aldehydes, epoxy, acrylates, free-radical basedagents, ethylene glycol diglycidyl ether (EGDE), poly(ethylene glycol)diglycidyl ether (PEGDE), or dicumyl peroxide (DCP). In one embodiment,from about 0.1% to about 15% w/w of cross-linking agent is addedrelative to the total dry weights of cross-linking agent and polymersadded when blending the ingredients (in one example, about 1% to about10%). During the curing process, substantially all of the cross-linkingagent is believed to react, leaving substantially no detectableunreacted cross-linking agent in the final film.

FIG. 6 is a cross-sectional view through one embodiment of an electrodeillustrating one embodiment of the membrane system 600. In thisparticular embodiment, the membrane system 600 comprises an electrodelayer 620, interference layer 630, enzyme layer 640, and a diffusionresistance layer 650, located around the core 610 of the electrode.

Described below are examples of layers that can be coated onto theelongated conductive body to form the membrane system.

Diffusion Resistance Layer

In some embodiments, the membrane system comprises a diffusionresistance layer, which may be disposed more distal to the elongatedconductive core than the other layers. A molar excess of glucoserelative to the amount of oxygen exists in blood, i.e., for every freeoxygen molecule in extracellular fluid, there are typically more than100 glucose molecules present (see, e.g., Updike et al., Diabetes Care5:207-21 (1982)). Accordingly, without a semipermeable membrane situatedover the enzyme layer to control the flux of glucose and oxygen, alinear response to glucose levels can or be obtained only up to about 40mg/dL. However, in a clinical setting, a linear response to glucoselevels is desirable up to at least about 500 mg/dL. The diffusionresistance layer serves to address these issues by controlling the fluxof oxygen and other analytes (for example, glucose) to the underlyingenzyme layer.

The diffusion resistance layer can include a semipermeable membrane thatcontrols the flux of oxygen and glucose to the underlying enzyme layer,thereby rendering oxygen in non-rate-limiting excess. As a result, theupper limit of linearity of glucose measurement is extended to a muchhigher value than that which is achieved without the diffusionresistance layer. In some embodiments, the diffusion resistance layerexhibits an oxygen-to-glucose permeability ratio of approximately 200:1,but in other embodiments the oxygen-to-glucose permeability ratio can beapproximately 100:1, 125:1, 130:1, 135:1, 150:1, 175:1, 225:1, 250:1,275:1, 300:1, or 500:1. As a result of the high oxygen-to-glucosepermeability ratio, one-dimensional reactant diffusion may providesufficient excess oxygen at all reasonable glucose and oxygenconcentrations found in the subcutaneous matrix (See Rhodes et al.,Anal. Chem., 66:1520-1529 (1994)).

In some embodiments, the diffusion resistance layer is formed of a basepolymer synthesized to include a polyurethane membrane with bothhydrophilic and hydrophobic regions to control the diffusion of glucoseand oxygen to an analyte sensor. A suitable hydrophobic polymercomponent can be a polyurethane or polyether urethane urea. Polyurethaneis a polymer produced by the condensation reaction of a diisocyanate anda difunctional hydroxyl-containing material. A polyurea is a polymerproduced by the condensation reaction of a diisocyanate and adifunctional amine-containing material. Diisocyanates that can be usedinclude aliphatic diisocyanates containing from about 4 to about 8methylene units. Diisocyanates containing cycloaliphatic moieties canalso be useful in the preparation of the polymer and copolymercomponents of the membranes of some embodiments. The material that formsthe basis of the hydrophobic matrix of the diffusion resistance layercan be any of those known in the art that is suitable for use asmembranes in sensor devices and as having sufficient permeability toallow relevant compounds to pass through it, for example, to allow anoxygen molecule to pass through the membrane from the sample underexamination in order to reach the active enzyme or electrochemicalelectrodes. Examples of materials which can be used to makenon-polyurethane type membranes include vinyl polymers, polyethers,polyesters, polyamides, inorganic polymers such as polysiloxanes andpolycarbosiloxanes, natural polymers such as cellulosic and proteinbased materials, and mixtures or combinations thereof.

In some embodiments, the diffusion resistance layer can comprise a blendof a base polymer (e.g., polyurethane) and one or more hydrophilicpolymers (e.g., PVA, PEG, polyacrylamide, acetates, PEO, PEA, PVP, andvariations thereof). It is contemplated that any of a variety ofcombination of polymers may be used to yield a blend with desiredglucose, oxygen, and interference permeability properties. For example,in some embodiments, the diffusion resistance layer can be formed from ablend of a silicone polycarbonate-urethane base polymer and a PVPhydrophilic polymer, but in other embodiments, a blend of apolyurethane, or another base polymer, and one or more hydrophilicpolymers can be used instead. In some of the embodiments involving theuse of PVP, the PVP portion of the polymer blend can comprise from about5% to about 50% by weight of the polymer blend, or from about 15% to20%, or from about 25% to 40%. It is contemplated that PVP of variousmolecular weights may be used. For example, in some embodiments, themolecular weight of the PVP used can be from about 25,000 daltons toabout 5,000,000 daltons, or from about 50,000 daltons to about 2,000,000daltons, or from 6,000,000 daltons to about 10,000,000 daltons.

In certain embodiments, the thickness of the diffusion resistance layercan be from about 0.05 microns or less to about 200 microns or more. Insome of these embodiments, the thickness of the diffusion resistancelayer can be from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4,0.45, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8 microns to about 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 19.5, 20, 30, 40, 50, 60, 70, 75, 80,85, 90, 95, or 100 microns. In some embodiments, the thickness of thediffusion resistance layer is from about 2, 2.5 or 3 microns to about3.5, 4, 4.5, or 5 microns in the case of a transcutaneously implantedsensor or from about 20 or 25 microns to about 40 or 50 microns in thecase of a wholly implanted sensor.

The description herein of the diffusion resistance layer is not intendedto be applicable only to the diffusion resistance layer; rather thedescription can also be applicable to any other layer of the membranesystem, such as the enzyme layer, electrode layer, or interferencelayer, for example.

Enzyme Layer

In some embodiments, the membrane system comprises an enzyme layer,which may be disposed more proximal to the elongated conductive corethan the diffusion resistance layer. The enzyme layer comprises acatalyst configured to react with an analyte. In one embodiment, theenzyme layer is an immobilized enzyme layer including glucose oxidase.In other embodiments, the enzyme layer can be impregnated with otheroxidases, for example, alcohol dehydrogenase, galactose oxidase,cholesterol oxidase, amino acid oxidase, alcohol oxidase, lactateoxidase, or uricase. For example, for an enzyme-based electrochemicalglucose sensor to perform well, the sensor's response should neither belimited by enzyme activity nor cofactor concentration.

In some embodiments, the catalyst (enzyme) can be impregnated orotherwise immobilized into the diffusion resistance layer such that aseparate enzyme layer is not required (e.g., wherein a unitary layer isprovided including the functionality of the diffusion resistance layerand enzyme layer). In some embodiments, the enzyme layer is formed froma polyurethane, for example, aqueous dispersions of colloidalpolyurethane polymers including the enzyme.

In some embodiments, the thickness of the enzyme layer can be from about0.01, 0.05, 0.6, 0.7, or 0.8 microns to about 1, 1.2, 1.4, 1.5, 1.6,1.8, 2, 2.1, 2.2, 2.5, 3, 4, 5, 10, 20, 30 40, 50, 60, 70, 80, 90, or100 microns. In some embodiments, the thickness of the enzyme layer isfrom about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,1.5, 2, 2.5, 3, 4, or 5 microns to about 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 19.5, 20, 25, or 30 microns, or from about 2, 2.5,or 3 microns to about 3.5, 4, 4.5, or 5 microns in the case of atranscutaneously implanted sensor or from about 6, 7, or 8 microns toabout 9, 10, 11, or 12 microns in the case of a wholly implanted sensor.

The description herein of the enzyme layer is not intended to beapplicable only to the enzyme layer; rather the description can also beapplicable to any other layer of the membrane system, such as thediffusion resistance layer, electrode layer, or interference layer, forexample.

Electrode Layer

In some embodiments, the membrane system comprises an electrode layer,which may be disposed more proximal to the elongated conductive corethan any other layer. The electrode layer is configured to facilitateelectrochemical reaction on the electroactive surface and can include asemipermeable coating for maintaining hydrophilicity at theelectrochemically reactive surfaces of the sensor interface. In otherembodiments, the functionality of the electrode layer can beincorporated into the diffusion resistance layer, so as to provide aunitary layer that includes the functionality of the diffusionresistance layer, enzyme layer, and/or electrode layer.

The electrode layer can enhance the stability of an adjacent layer byprotecting and supporting the material that makes up the adjacent layer.The electrode layer may also assist in stabilizing the operation of thedevice by overcoming electrode start-up problems and drifting problemscaused by inadequate electrolyte. The buffered electrolyte solutioncontained in the electrode layer may also protect against pH-mediateddamage that can result from the formation of a large pH gradient betweenthe substantially hydrophobic interference layer and the electrodes dueto the electrochemical activity of the electrodes.

In one embodiment, the electrode domain includes hydrophilic polymerfilm (e.g., a flexible, water-swellable, hydrogel) having a “dry film”thickness of from about 0.05 microns or less to about 20 microns ormore, or from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45,0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, or from about 3,2.5, 2, or 1 microns, or less, to about 3.5, 4, 4.5, or 5 microns ormore. “Dry film” thickness refers to the thickness of a cured film castfrom a coating formulation by standard coating techniques.

In certain embodiments, the electrode layer can be formed of a curablemixture of a urethane polymer and a hydrophilic polymer. In some ofthese embodiments, coatings are formed of a polyurethane polymer havinganionic carboxylate functional groups and non-ionic hydrophilicpolyether segments, wherein the polyurethane polymer undergoesaggregation with a water-soluble carbodiimide (e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the presence ofpolyvinylpyrrolidone and cured at a moderate temperature of about 50° C.

Particularly suitable for this purpose are aqueous dispersions offully-reacted colloidal polyurethane polymers having cross-linkablecarboxyl functionality (e.g., BAYBOND®; Mobay Corporation). Thesepolymers are supplied in dispersion grades having apolycarbonate-polyurethane backbone containing carboxylate groupsidentified as W-121 and XW-123; and a polyester-polyurethane backbonecontaining carboxylate groups, identified as W-110-2. In someembodiments, BAYBOND® 123, an aqueous anionic dispersion of an aliphaticpolycarbonate urethane polymer sold as a 35 weight percent solution inwater and co-solvent N-methyl-2-pyrrolidone, can be used.

In some embodiments, the electrode layer is formed from a hydrophilicpolymer that renders the electrode layer substantially more hydrophilicthan an overlying layer (e.g., interference layer, enzyme layer). Suchhydrophilic polymers can include, a polyamide, a polylactone, apolyimide, a polylactam, a functionalized polyamide, a functionalizedpolylactone, a functionalized polyimide, a functionalized polylactam orcombinations thereof, for example.

In some embodiments, the electrode layer is formed primarily from ahydrophilic polymer, and in some of these embodiments, the electrodelayer is formed substantially from PVP. PVP is a hydrophilicwater-soluble polymer and is available commercially in a range ofviscosity grades and average molecular weights ranging from about 18,000to about 500,000, under the PVP K® homopolymer series by BASF Wyandotteand by GAF Corporation. In certain embodiments, a PVP homopolymer havingan average molecular weight of about 360,000 identified as PVP-K90 (BASFWyandotte) can be used to form the electrode layer. Also suitable arehydrophilic, film-forming copolymers of N-vinylpyrrolidone, such as acopolymer of N-vinylpyrrolidone and vinyl acetate, a copolymer ofN-vinylpyrrolidone, ethylmethacrylate and methacrylic acid monomers, andthe like.

In certain embodiments, the electrode layer is formed entirely from ahydrophilic polymer. Useful hydrophilic polymers contemplated include,but are not limited to, poly-N-vinylpyrrolidone,poly-N-vinyl-2-piperidone, poly-N-vinyl-2-caprolactam,poly-N-vinyl-3-methyl-2-caprolactam, poly-N-vinyl-3-methyl-2-piperidone,poly-N-vinyl-4-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-caprolactam,poly-N-vinyl-3-ethyl-2-pyrrolidone,poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole,poly-N,N-dimethylacrylamide, polyvinyl alcohol, polyacrylic acid,polyethylene oxide, poly-2-ethyl-oxazoline, copolymers thereof andmixtures thereof. A blend of two or more hydrophilic polymers can bepreferred in some embodiments.

It is contemplated that in certain embodiments, the hydrophilic polymerused may not be crosslinked, but in other embodiments, crosslinking maybe used and achieved by any of a variety of methods, for example, byadding a crosslinking agent. In some embodiments, a polyurethane polymercan be crosslinked in the presence of PVP by preparing a premix of thepolymers and adding a cross-linking agent just prior to the productionof the membrane. Suitable cross-linking agents contemplated include, butare not limited to, carbodiimides (e.g.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, UCARLNK®.XL-25 (Union Carbide)), epoxides and melamine/formaldehyde resins.Alternatively, it is also contemplated that crosslinking can be achievedby irradiation at a wavelength sufficient to promote crosslinkingbetween the hydrophilic polymer molecules, which is believed to create amore tortuous diffusion path through the layer.

The flexibility and hardness of the coating can be varied as desired byvarying the dry weight solids of the components in the coatingformulation. The term “dry weight solids” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to the dry weightpercent based on the total coating composition after the time thecrosslinker is included. In one embodiment, a coating formulation cancontain about 6 to about 20 dry weight percent, or about 8 dry weightpercent, PVP; about 3 to about 10 dry weight percent, or about 5 dryweight percent cross-linking agent; and about 70 to about 91 weightpercent, or about 87 weight percent of a polyurethane polymer, such as apolycarbonate-polyurethane polymer, for example. The reaction product ofsuch a coating formulation is referred to herein as a water-swellablecross-linked matrix of polyurethane and PVP.

In some embodiments, underlying the electrode layer is an electrolytephase that when hydrated is a free-fluid phase including a solutioncontaining at least one compound, typically a soluble chloride salt,which conducts electric current. In one embodiment wherein the membranesystem is used with a glucose sensor such as is described herein, theelectrolyte phase flows over the electrodes and is in contact with theelectrode layer. It is contemplated that certain embodiments can use anysuitable electrolyte solution, including standard, commerciallyavailable solutions. Generally, the electrolyte phase can have the sameosmotic pressure or a lower osmotic pressure than the sample beinganalyzed. In some embodiments, the electrolyte phase comprises normalsaline.

The description herein of the electrode layer is not intended to beapplicable only to the electrode layer; rather the description can alsobe applicable to any other layer of the membrane system, such as thediffusion resistance layer, enzyme layer, or interference layer, forexample.

Interference Layer

In some embodiments, the membrane system may comprise an interferencelayer configured to substantially reduce the permeation of one or moreinterferents into the electrochemically reactive surfaces. Theinterference layer may be configured to be substantially less permeableto one or more of the interferents than to the measured species. It isalso contemplated that in some embodiments, where interferent blockingmay be provided by the diffusion resistance layer (e.g., via asurface-active group-containing polymer of the diffusion resistancelayer), a separate interference layer may not be used.

In some embodiments, the interference layer is formed from asilicone-containing polymer, such as a polyurethane containing silicone,or a silicone polymer. While not wishing to be bound by theory, it isbelieved that, in order for an enzyme-based glucose sensor to functionproperly, glucose would not have to permeate the interference layer,where the interference layer is located more proximal to theelectroactive surfaces than the enzyme layer. Accordingly, in someembodiments, a silicone-containing interference layer, comprising agreater percentage of silicone by weight than the diffusion resistancelayer, can be used without substantially affecting glucose concentrationmeasurements. For example, in some embodiments, the silicone-containinginterference layer can comprise a polymer with a high percentage ofsilicone (e.g., from about 25%, 30%, 35%, 40%, 45%, or 50% to about 60%,70%, 80%, 90% or 95%).

In one embodiment, the interference layer can include ionic componentsincorporated into a polymeric matrix to reduce the permeability of theinterference layer to ionic interferents having the same charge as theionic components. In another embodiment, the interference layer caninclude a catalyst (for example, peroxidase) for catalyzing a reactionthat removes interferents.

In certain embodiments, the interference layer can include a thinmembrane that is designed to limit diffusion of certain species, forexample, those greater than 34 kD in molecular weight. In theseembodiments, the interference layer permits certain substances (forexample, hydrogen peroxide) that are to be measured by the electrodes topass through, and prevents passage of other substances, such aspotentially interfering substances. In one embodiment, the interferencelayer is constructed of polyurethane. In an alternative embodiment, theinterference layer comprises a high oxygen soluble polymer, such assilicone.

In some embodiments, the interference layer is formed from one or morecellulosic derivatives. In general, cellulosic derivatives can includepolymers such as cellulose acetate, cellulose acetate butyrate,2-hydroxyethyl cellulose, cellulose acetate phthalate, cellulose acetatepropionate, cellulose acetate trimellitate, or blends and combinationsthereof.

In some alternative embodiments, other polymer types that can beutilized as a base material for the interference layer includepolyurethanes, polymers having pendant ionic groups, and polymers havingcontrolled pore size, for example. In one such alternative embodiment,the interference layer includes a thin, hydrophobic membrane that isnon-swellable and restricts diffusion of low molecular weight species.The interference layer is permeable to relatively low molecular weightsubstances, such as hydrogen peroxide, but restricts the passage ofhigher molecular weight substances, including glucose and ascorbic acid.

It is contemplated that in some embodiments, the thickness of theinterference layer can be from about 0.01 microns or less to about 20microns or more. In some of these embodiments, the thickness of theinterference layer can be from about 0.01, 0.05, 0.1, 0.15, 0.2, 0.25,0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns.In some of these embodiments, the thickness of the interference layercan be from about 0.2, 0.4, 0.5, or 0.6, microns to about 0.8, 0.9, 1,1.5, 2, 3, or 4 microns.

The description herein of the interference layer is not intended to beapplicable only to the interference layer; rather the description canalso be applicable to any other layer of the membrane system, such asthe diffusion resistance layer, enzyme layer, or electrode layer, forexample.

Therapeutic Agents

A variety of therapeutic (bioactive) agents can be used with the analytesensor system. In some embodiments, the therapeutic agent is ananticoagulant for preventing coagulation within or on the sensor. Insome embodiments, the therapeutic agent is an antimicrobial, such as butnot limited to an antibiotic or antifungal compound. In someembodiments, the therapeutic agent is an antiseptic and/or disinfectant.Therapeutic agents can be used alone or in combination of two or moreagents. The therapeutic agents can be dispersed throughout the materialof the sensor. In some embodiments, the membrane system can include atherapeutic agent that is incorporated into a portion of the membranesystem, or which is incorporated into the device and adapted to diffusethrough the membrane.

There are a variety of systems and methods by which the therapeuticagent can be incorporated into the membrane system. In some embodiments,the therapeutic agent is incorporated at the time of manufacture of themembrane system. For example, the therapeutic agent can be blended priorto curing the membrane system. In other embodiments, the therapeuticagent is incorporated subsequent to membrane system manufacture, forexample, by coating, imbibing, solvent-casting, or sorption of thebioactive agent into the membrane system. Although the therapeutic agentcan be incorporated into the membrane system, in some embodiments thetherapeutic agent can be administered concurrently with, prior to, orafter insertion of the device intravascularly, for example, by oraladministration, or locally, for example, by subcutaneous injection nearthe implantation site. In some embodiments, a combination of therapeuticagent incorporated in the membrane system and therapeutic agentadministration locally and/or systemically can be used.

Mounting Unit

As illustrated in FIG. 1, the sensor device 100 may include askin-contacting mounting unit 150 configured to be secured to a host. Insome embodiments, the mounting unit 150 comprises a base 152 adapted forfastening to a host's skin. The base 152 can be formed from a variety ofhard or soft materials and may comprise a low profile for minimizingprotrusion of the sensor device from the host during use. In someembodiments, the base 152 is formed at least partially from a flexiblematerial configured to conform to skin contour, so as to reduce oreliminate motion-related artifacts associated with movement by the host.To achieve this flexibility, the material chosen may have a flexuralmodulus of less than about 5,000 MPa, or less than about 1,000 MPa, orless than about 500 MPa, or less than about 100 MPa, or less than about50 MPa, as determined by ASTM D790. The base 152 may have a preselectedthickness that allows the material to flex with movements of the skin.When a transcutaneous sensor device is inserted into the host, variousmovements of the sensor (for example, relative movement between the invivo portion and the ex vivo portion, movement of the skin, and/ormovement within the host (dermis or subcutaneous)) can create stresseson the device and produce noise in the sensor signal. It is believedthat even small movements of the skin can translate to discomfort and/ormotion-related artifacts, which can be reduced or obviated by a flexibleor articulated base. Thus, by providing flexibility and/or articulationof the sensor device against the host's skin, better conformity of thesensor device to the regular use and movements of the host can beachieved. Flexibility or articulation is believed to increase adhesion(with the use of an adhesive layer) of the mounting unit 150 onto theskin 180, thereby decreasing motion-related artifacts that can otherwisetranslate from the host's movements and reduce sensor performance.

In certain embodiments, the base 152 of the mounting unit 150 isprovided with an adhesive material or adhesive layer 154, also referredto as an adhesive pad, preferably disposed on the mounting unit's bottomsurface and may including a releasable backing layer. Thus, removing thebacking layer and pressing the base 152 of the mounting unit 150 ontothe host's skin 180 adheres the mounting unit 150 to the host's skin180. Appropriate adhesive layers can be chosen and designed to stretch,elongate, conform to, and/or aerate the region (e.g. host's skin).

Any of a variety of adhesive layers appropriate for adhesion to thehost's skin can be used. For example, in certain embodiments, theadhesive layer is formed from spun-laced, open- or closed-cell foam,and/or non-woven fibers, and includes an adhesive disposed thereon. Insome embodiments, a double-sided adhesive layer is used to adhere themounting unit to the host's skin. In other embodiments, the adhesivelayer includes a foam layer, for example, a layer wherein the foam isdisposed between the adhesive layer's side edges and acts as a shockabsorber. In certain embodiments, the adhesive layer is formed of awaterproof material.

In some embodiments, the surface area of the adhesive layer is greaterthan the surface area of the bottom surface of the mounting unit's base.Alternatively, the adhesive layer can be sized with substantially thesame surface area as the bottom surface of the base. The adhesive layermay have a surface area on the side to be mounted on the host's skinthat is greater than about 1, 1.25, 1.5, 1.75, 2, 2.25, or 2.5 times thesurface area of the bottom surface of the mounting unit base. Such agreater surface area can increase adhesion between the mounting unit andthe host's skin, minimize movement between the mounting unit and thehost's skin, and/or protect the wound exit-site (sensor insertion site)from environmental and/or biological contamination. In some alternativeembodiments, however, the adhesive layer can be smaller in surface areathan the back surface assuming a sufficient adhesion can beaccomplished.

As illustrated in FIGS. 3A-3C, in certain embodiments, the mounting unit350 may comprise contacts 358 for providing a stable mechanical andelectrical connection between the electrodes and the sensor electronicsunit, which is described in greater detail elsewhere herein. A stableconnection can be provided using a variety of known methods, forexample, raised (e.g., domed) metallic contacts, cantilevered fingers,pogo pins, or the like. In certain embodiments, the contacts are formedfrom a conductive elastomeric material, such as a carbon blackelastomer, through which the electrodes extend. Conductive elastomersmay be preferred in some instances because their resilient propertiescreate a natural compression against mutually engaging contacts, therebyproviding a secure press fit therewith. In other embodiments, thecontacts are formed from a stiff plastic material, which is shaped tocomply upon application of pressure. Non-metallic contacts can bepreferred in some instances because of their seamless manufacturability,robustness to thermal compression, non-corrosive surfaces, and nativeresistance to electrostatic discharge (ESD) damage due to theirhigher-than-metal resistance. In still other embodiments, the mountingunit does not comprise contacts. Instead, the electrodes may be directlyhardwired to the sensor electronics unit, to provide electricalconnection prior to, during, and/or after sensor insertion.

FIG. 8A illustrates one embodiment of a mounting unit 850 with a raisedupper surface 852, formed of an elastomeric material and adapted toreceive a pressure from a user for insertion of the in vivo portion ofthe sensor device. In some embodiments, the raised upper surface 852 maybe detachably attached to a sensor unit 814 comprising a tissue piercingelement 810 and a sensor body 830, which is comprised of one or moreelectrodes with a membrane disposed thereon. While the upper surface 852is shown here with a domed shape, any of a variety of other shapes maybe used, such as a frusto-conical shape, for example. As shown in FIG.8A, the sensor device 800 may be a self-containing sterile field and besupplied to the user with the sensor unit 814 in a retracted state,i.e., with the in vivo portion hidden inside the sensor device 800. Thisconfiguration allows the user to place the sensor device 800 on the skinwithout the possibility of observing the sensor unit 814. With thesensor unit 814 hidden, some of the fear to the user of using the sensordevice may be abated, thereby making the insertion of the sensor unit814 less problematic. To use the sensor device 800, the user first peelsthe sensor device 800 away from a backing layer 822. With the backinglayer 822 peeled away, a sterile bottom surface 824 of the sensor device800 is exposed, such that further sterilization of the sensor device'scontact surface 824 with the host's skin may not be required. The bottomsurface 824 of the sensor device comprises an adhesive that readilyallows the mounting unit to be adhered to the skin. After the sensordevice 800 has been adhered to the host's skin, the sensor unit 814 isintroduced into the host's tissue, as the user presses the upper surface(e.g., the dome) of the mounting unit 850 downwards to cause the in vivoportion of the sensor device to penetrate the host's skin. In certainembodiments, after pressure is released from the upper surface 852, theupper surface 852 becomes detached from the sensor unit 814, as itresumes its normal convex shape, and as the sensor body 830 remainsembedded in the host's tissue. In alternative embodiments, instead of(or in addition to) using a downward pressure from the top of the uppersurface 852 to cause collapse of the upper surface 852, the sensordevice 800 may be configured such that pressure from other directionscan be used. For example, the sensor device 800 may be equipped with twodiametrically opposed tabs, placed at the edges of the upper surface852, that are to be pulled in opposite directions to cause collapse ofthe upper surface 852, thereby resulting in the deployment of the sensorbody 830. In still other embodiments, other mechanisms not relyingentirely on pressure applied by the user can also be employed. Forinstance, in one embodiment, the upper surface 852 may be formed of amaterial (e.g., a shape memory material) that is conducive to inducingthe sensor device 800 a collapsed state. In this embodiment, removal ofthe backing layer 822 and a mere slight touch by the user may besufficient to cause collapse of the upper surface 852 and deployment ofthe sensor body 830.

In some embodiments, the raised upper surface 852 and the bottom surface824 are configured to be readily peeled away by the user after insertionof the sensor unit 814. In other embodiments, the raised upper surface852 and/or the bottom surface 824 are configured to remain with thesensor unit 814 after insertion. In further embodiments, the raisedupper surface 852 may be configured to remain in a collapsed state afterthe insertion process. This configuration may be preferable in someinstances, because the resulting lower profile of the sensor device 800may reduce the risk of movement of the upper surface 852 (e.g., from anaccidental bump by the host), which could translate to movement of thesensor unit 814 and thus create motion-related artifacts. Any of avariety of mechanism may be used to achieve the collapsed stateconfiguration. For example, as illustrated in FIG. 8B, in oneembodiment, the sensor device 800 may comprise a locking mechanism inthe form of a latch member 872 attached to the bottom side of the uppersurface 852 and a locking receptacle 874 that is part of a base 878. Thelatch member 872 and the locking receptacle 874 are configured to matewith each other during the sensor insertion process, thereby bringingcontacts 882, 884 together, so that an electrical connection between thesensor unit and the sensor electronics is made. In some embodiments, thebase 878 forms at least a portion of the sensor electronics unit and/orcomprises a transmitter that is configured to transmit sensor data to aremote computer system.

To enhance column strength and stability of the in vivo portion of thesensor device, some of the mounting units described herein, such asthose illustrated in FIGS. 8A and 8B, may comprise a guiding portion 862configured to provide guidance and support to the in vivo portion of thesensor device 800 as it is inserted through the skin of the host. It hasbeen found that the largest force needed for the insertion processinvolves the force required to push the tip of the sensor device 800through the skin. Once a portion of the sensor device 800 has penetratedthrough the skin, an opening is created by the tissue piercing element810 that permits the rest of the sensor device 800 to pass through theskin with minimal resistance. Additionally, as this occurs, the tissuesurrounding the sensor device 800 presses against that portion of thesensor device 800 and thus provides it with additional column strength.The guiding portion 862 may have any of a variety of configurations. Forexample, as illustrated in FIG. 8A, in some embodiments, the guidingportion 862 may have a configuration of a spiraling spring, throughwhich the tissue piercing element and/or sensor body may pass.Alternatively, the guiding portion 862 may have a tube configuration, asillustrated in FIG. 8C. In this particular embodiment, a nested tubemechanism is used which may include an inner tubular member 864, andoptionally one or more intermediate tubular members 866, nested withinthe lumen of an outer tubular member 868. The sensor unit 814 isattached to the inner tubular member and configured to be movedlongitudinally through the skin, as the inner tubular member 864 isadvanced into the intermediate tubular member 866, and into the outertubular member 868, as illustrated in FIG. 8D. In further embodiments,the tubular members may comprise latches configured to lock the tubularmembers in place, after the inner tubular member 864 has been advancedinto the intermediate tubular member 866 and the outer tubular member868, to prevent the sensor unit 814 from withdrawing back into itsoriginal retracted position.

As illustrated in FIG. 3E, in some embodiments, the mounting unit 350 isadapted to be united with a sensor electronics unit 390, which isdescribed in greater detail elsewhere herein, to collectively form anon-skin unit. In certain embodiments, the sensor electronics unit can bedetachable from (e.g., releasably attached to) the mounting unit, but inother embodiments, the sensor electronics unit is integral with and notdetachable from the mounting unit. The on-skin unit may further includea user interface which displays sensor information to the host via anyof a variety of methods for displaying sensor information, such as anLED, an LCD screen, computer-generated audible information, tactilesignals, or other user interface types, for example. The term “userinterface” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to any method of communication to the user.

In some embodiments such as shown in FIG. 9A, the user interfaceincludes a screen 930 that shows thresholds, including a high threshold900 and a low threshold 902, which represent boundaries betweenclinically safe and clinically risky conditions for the patients. In oneexemplary embodiment, a normal glucose threshold for a glucose sensor isset from about 100 to 160 mg/dL, and the clinical risk zones 904 areillustrated outside of these thresholds. In alternative embodiments, thenormal glucose threshold is from about 80 to about 200 mg/dL, from about55 to about 220 mg/dL, or other threshold that can be set by themanufacturer, physician, patient, computer program, or the like.Although a few examples of glucose thresholds are given for a glucosesensor, the setting of any analyte threshold is not limited by thepreferred embodiments.

In some embodiments, the screen 930 that shows clinical risk zones 904(also referred to as danger zones, through shading, gradients) or othergraphical illustrations that indicate areas of increasing clinical risk.Clinical risk zones 904 can be set by a manufacturer, customized by adoctor, and/or set by a user via buttons 932, for example. In someembodiments, the danger zone 904 can be continuously shown on the screen930, or the danger zone can appear when the measured and/or estimatedanalyte values fall into the danger zone 904. Additional information canbe displayed on the screen, such as an estimated time to clinical risk.In some embodiments, the danger zone can be divided into levels ofdanger (for example, low, medium, and high) and/or can be color-coded(for example, yellow, orange, and red) or otherwise illustrated toindicate the level of danger to the patient. Additionally, the screen orportion of the screen can dynamically change colors or illustrationsthat represent a nearness to the clinical risk and/or a severity ofclinical risk.

In some embodiments, such as that shown in FIG. 9A, the screen 930displays a trend graph of measured analyte data 906. Measured analytedata can be smoothed and calibrated such as described in more detailelsewhere herein. Measured analyte data can be displayed for a certaintime period (for example, previous 1 hour, 3 hours, 9 hours, etc.) Insome embodiments, the user can toggle through screens using buttons 932to view the measured analyte data for different time periods, usingdifferent formats, or to view certain analyte values (for example, highsand lows).

In some embodiments such as shown in FIG. 9A, the screen 930 displaysestimated analyte data 908 using dots. In this illustration, the size ofthe dots can represent the confidence of the estimation, a variation ofestimated values, or the like. For example, as the time gets fartheraway from the present (t=0) the confidence level in the accuracy of theestimation can decline. In some alternative embodiments, dashed lines,symbols, icons, or the like can be used to represent the estimatedanalyte values. In some alternative embodiments, shaded regions, colors,patterns, or the like can also be used to represent the estimatedanalyte values, a confidence in those values, and/or a variation ofthose values.

FIG. 9B is an illustration of a user interface in another embodimentshowing a representation of analyte concentration and directional trendusing a gradient bar. In this embodiment, the screen 930 illustrates themeasured analyte values and estimated analyte values in a simple buteffective manner that communicates valuable analyte information to theuser. In this embodiment, a gradient bar 910 is provided that includesthresholds 912 set at highs and lows such as described in more detailwith reference to FIG. 9A, above. Additionally, colors, shading, orother graphical illustration can be present to represent danger zones914 on the gradient bar 910 such as described in more detail withreference to FIG. 9A, above.

The measured analyte value is represented on the gradient bar 910 by amarker 916, such as a darkened or colored bar. By representing themeasured analyte value with a bar 916, a low-resolution analyte value ispresented to the user (for example, within a range of values). Forexample, each segment on the gradient bar 916 can represent about 10mg/dL of glucose concentration. As another example, each segment candynamically represent the range of values that fall within the “A” and“B” regions of the Clarke Error Grid. While not wishing to be bound bytheory, it is believe that inaccuracies known both in reference analytemonitors and/or continuous analyte sensors are likely due to knownvariables such as described in more detail elsewhere herein, and can bede-emphasized such that a user focuses on proactive care of thecondition, rather than inconsequential discrepancies within and betweenreference analyte monitors and continuous analyte sensors.

Additionally, the representative gradient bar communicates thedirectional trend of the analyte concentration to the user in a simpleand effective manner, namely by a directional arrow 918. For example, inconventional diabetic blood glucose monitoring, a person with diabetesobtains a blood sample and measures the glucose concentration using atest strip, or the like. Unfortunately, this information does not tellthe person with diabetes whether the blood glucose concentration isrising or falling. Rising or falling directional trend information canbe particularly important in a situation such as illustrated in FIG. 9B,wherein if the user does not know that the glucose concentration isrising, he/she may assume that the glucose concentration is falling andnot attend to his/her condition. However, because rising directionaltrend information 918 is provided, the person with diabetes can preemptthe clinical risk by attending to his/her condition (for example,administer insulin). Estimated analyte data can be incorporated into thedirectional trend information by characteristics of the arrow, forexample, size, color, flash speed, or the like.

In some embodiments, the gradient bar can be a vertical instead ofhorizontal bar. In some embodiments, a gradient fill can be used torepresent analyte concentration, variation, or clinical risk, forexample. In some embodiments, the bar graph includes color, for examplethe center can be green in the safe zone that graduates to red in thedanger zones; this can be in addition to or in place of the dividedsegments. In some embodiments, the segments of the bar graph are clearlydivided by lines; however color, gradation, or the like can be used torepresent areas of the bar graph. In some embodiments, the directionalarrow can be represented by a cascading level of arrows to a representslow or rapid rate of change. In some embodiments, the directional arrowcan be flashing to represent movement or pending danger.

The screen 930 of FIG. 9B can further comprise a numericalrepresentation of analyte concentration, date, time, or otherinformation to be communicated to the patient. However, a user canadvantageously extrapolate information helpful for his/her conditionusing the simple and effective representation of this embodiment shownin FIG. 9B, without reading a numeric representation of his/her analyteconcentration.

In some alternative embodiments, a trend graph or gradient bar, a dial,pie chart, or other visual representation can provide analyte data usingshading, colors, patterns, icons, animation, or the like.

In some embodiments, the user interface includes a color display elementthat is capable of reversibly changing colors in accordance with changesin analyte concentration (e.g., glucose concentration). For example, thecolor display element may be configured to exhibit a green color when aglucose concentration is within a predetermined target range.Furthermore, if the sensor device detects hyperglycemia (i.e., a glucoseconcentration greater than those within the target range), it may changeto another color (e.g., a dark blue color). Conversely, if the sensordevice detects a hypoglycemic event (i.e., a glucose concentration lessthose within the target range), it may change to yet another color(e.g., a red color). The color display element may be also be configuredto provide a color gradation scheme that represents a degree of changein glucose concentration. By way of example, a color gradation schemefrom red (for severe hypoglycemia) to yellow (for mild hypoglycemia) maybe used for low glucose concentration levels. Correspondingly, a colorgradation scheme from dark blue (for severe hyperglycemia) to light blue(for mild hyperglycemia) may be used for high glucose concentrationlevels. Any of a variety of color display elements may be used, such asan LED, an LCD, or a color changing material, for example. In someinstances, an LED may be desirable, because of its low energyconsumption, small size, and robustness. However, in other instances, alow-powered or non-powered mechanism may be desirable. Materials thatinclude a chemical composition having a color indicator (e.g.,4-Aminoantipyrine, N-ethyl-N-(2-hydroxy-3-sulfopropyl)-3,5dimethoxyaniline) may be used to trigger the color change.

Although in some embodiments, the sensor device may be capable ofdisplaying three or more colors (e.g., a first color for hyperglycemia,a second color for eugylcemia, and a third color for hypoglycemia) fordifferent analyte concentrations, in other embodiments, for simplicity,the sensor device may be designed to display one of two colors and toprovide warning to the user about a specific condition (e.g.,hypoglycemia). For example, the sensor device may be designed to displaya first color for all glucose levels other than hypoglycemia and todisplay a second color for hypoglycemia. In some embodiments, colorchange transformation may take place in response to an event involvingboth analyte concentration and rate of change of analyte concentration.For example, for a sensor device designed to provide warning to the userof a hypoglycemia event, the color display element may designed totrigger color change when both the rate of change of glucoseconcentration is less than or equal to about −4 mg dL⁻¹ min⁻¹ (e.g.,−4.5 mg dL⁻¹ min⁻¹) and the glucose concentration is less than or equalto about 100 mg dL⁻¹. It is contemplated that the sensor device may bedesigned to respond via color change to other events, such as acondition in which the rate of change of glucose concentration is lessthan or equal to about −3 mg dL⁻¹ min⁻¹ and the glucose concentration isless than or equal to about 90 mg dL⁻¹, a condition in which the rate ofchange of glucose concentration is less than or equal to about −2 mgdL⁻¹ min⁻¹ and the glucose concentration is less than or equal to about75 mg dL⁻¹, a condition in which the rate of change of glucoseconcentration is less than or equal to about −1 mg dL⁻¹ min⁻¹ and theglucose concentration is less than or equal to about 70 mg dL⁻¹, and acondition in which the glucose concentration is less than or equal toabout 50 mg dL⁻¹ regardless of the rate of change of glucoseconcentration. It should be understood that the conditions provideherein are merely exemplary, and that other conditions may be used inaddition to (or in place of) the above-listed conditions

As previously described, in some embodiments, the on-skin unit mayinclude the sensor electronics unit, which provides systems and methodsfor processing sensor data. The sensor electronics unit generallyincludes hardware, firmware, and/or software that enable measurement oflevels of the analyte via the sensor and that enable audible, tactile,or visible communication or display of the sensor data. Accordingly, thesensor electronics unit enables processing of and displaying of sensordata. For example, the sensor electronics unit may include programmingfor retrospectively and/or prospectively initiating a calibration,converting sensor data, updating the calibration, and/or evaluating thecalibration for the analyte sensor.

The sensor electronics unit can be affixed to a printed circuit board(PCB), or the like, and can take a variety of forms. For example, thesensor electronics unit can take the form of an integrated circuit (IC),such as an Application-Specific Integrated Circuit (ASIC), amicrocontroller, or a processor, such as described in more detail hereinwith reference to sensor electronics unit and/or remote computer system.In some embodiments, the sensor electronics unit comprises a digitalfilter, for example, an IIR or FIR filter, configured to smooth the rawdata stream from the A/D converter.

In an embodiment wherein the sensor electronics unit is at leastpartially removably attached to the on-skin unit, a system can beprovided to enable docking of the sensor electronics unit, and therebydownloading and viewing of the sensor data on a remote device, e.g., asensor receiver, PDA, computer system, docking station, insulin pump, ahearing aid, or the like. In one such embodiment, the on-skin unitprovides numerical sensor information; additionally, a user can dock theremovable sensor electronics unit of the on-skin unit onto the remotedevice to view additional information (e.g., graphical sensorinformation). Alternatively, the on-skin unit can be used instead of theremote computer system to store and process all of the necessary datauntil a remote computer system is available for the transfer of data (orenable a system that does not require a remote computer system). In somealternative embodiments, the on-skin unit communicates with the remotecomputer system via a cable, radio frequency, optical, inductivecoupling, infrared, microwave or other known methods of datatransmission. In one such exemplary embodiment, the on-skin unit isconfigured to communicate with the remote computer system when“requested” or interrogated by the remote computer system. For example,when the remote computer system is held in close proximity (e.g., within3 meters) of the on-skin unit, transmission of sensor data can berequested (e.g., using data transmission methods such as inductivecoupling, optical, infrared, or the like.)

An on-skin unit with data communication directly therefrom can provideimproved convenience to the patient (e.g., there is no need for thepatient to keep track of the remote computer system and maintain itwithin a predetermined range of the sensor at all times) and increasedease of use (e.g., fewer parts for the patient to understand, program,and/or carry). Additionally, circumstances exist (e.g., on airplanes,while swimming, etc.) where a patient may not be able to carry a remotecomputer system or during which time certain wireless transmissions maynot be permitted; however, with an on-skin user-communicating unit, thepatient will not be without critical sensor data.

FIG. 10A is a perspective view of one embodiment of a sensor systemwhich includes a mounting unit in the form of a disposable thin laminatesensor housing. The laminate sensor housing 1000 includes an adhesivelayer 1008 and a plurality of layers (see FIG. 10B) beneath housingcover 1054. The sensor housing 1000 is adhered to the skin by theadhesive layer 1008, which is described in more detail elsewhere herein.The laminate housing may be formed from a plurality of thin layerssecured together to form an overall thin housing.

In some embodiments, the overall height of the laminate housing is nomore than about 0.5 inches in its smallest dimension, or no more thanabout 0.25 inches in its smallest dimension, or no more than about 0.125inches in its smallest dimension. In some embodiments, the overallheight of the laminate housing is from about 0.075 inches or less, 0.08inches or less, 0.09 inches or less, 0.1 inches or less, or 0.125 inchesor less to about 0.15 inches or more, 0.2 inches or more, 0.225 inchesor more, or 0.25 inches or more; while the length and/or width of thelaminate housing can be substantially greater, for example, at leastabout 0.25 inches or more, 0.5 inches or more, 1 inch or more or 1.5inches or more. In some embodiments, the aspect ratio of the laminatehousing is at least about 10:1, 15:1, 20:1, 30:1, 40:1, or 50:1.

FIG. 10B is cut-away side cross-sectional view of the thin, laminate,flexible sensor system in one embodiment. As shown, the layers aresecured together, and the sensor body and sensor electronics unit areelectrically connected. Although a particular order of layers isillustrated in FIG. 10B, in other embodiments, the layers can berepositioned relative to one another, integrated with one another,and/or otherwise modified while still enabling sensor function andperformance.

In some embodiments, the sensor device includes a sensor body 1020configured to continuously measure an analyte concentration in a hostand a sensor housing 1000 configured to receive the sensor body. Thesensor body 1020 is inserted into the host's subcutaneous tissue bypress insertion as described in more detail elsewhere herein. The sensorhousing 1000 may be adapted for placement adjacent to the host's skinand includes multiple layers (e.g., a laminate housing) including one ormore of the following functional components: electronics operativelyconnected to the sensor body 1020 and including a processor moduleconfigured to provide a signal associated with the analyte concentrationin the host, a power source configured to power at least one of thesensor body and the electronics, an antenna configured for radiating orreceiving an RF transmission, and an adhesive layer configured to adherethe housing to the host's skin. In some embodiments, the sensor housing1000 is a substantially planar, flexible, laminate housing.

In some embodiments, the sensor housing includes a power sourceassociated with (e.g., located in or on) a substantially planar,flexible substrate. In some embodiments, the laminate sensor housing1000 includes a flexible battery 1044, which provides a source of powerfor the sensor body and/or electronics, as described in more detailelsewhere herein. Although the battery 1044 is shown as a layer adjacentto the adhesive layer in the illustrated exemplary embodiment, theflexible battery can be disposed in the adhesive layer and/or laminatedto the adhesive layer, including a configuration wherein other layersare located between the flexible battery and the adhesive layer. In someembodiments, the flexible battery is no more than about 0.2, 0.1, 0.05,0.03, 0.02, or 0.01 inches in its smallest dimension. In someembodiments, the flexible battery is a thin, flexible battery and has anaspect ratio of at least about 10:1. In some alternative embodiments,the flexible battery is shaped to conform to at least a part of thehousing cover. In some embodiments, the battery is formed in a spiralconfiguration. In some embodiments, the battery is combined into anotherfunctional layer of the laminate housing; for example, it may not be adistinct layer, per se.

In some embodiments, the laminate sensor housing 1000 includes aconductive contact layer 1028, which provides an electrical connectionbetween the sensor body 1020 and sensor electronics (e.g., electricalcontacts on the flexible circuit board 1050). In some embodiments, theconductive contact layer 1028 forms at least a portion of theelectronics or electronics component. In some embodiments, theconductive contact layer includes one or more discrete electricalcontacts configured to electrically connect one or more electrodes ofthe sensor body to the sensor electronics (e.g., deposited thereon,provided individually as described elsewhere herein, or the like).

Although the illustrated embodiments show the conductive contact layerlocated between the battery and the flexible circuit board, theconductive contact layer can be located in any location that allows thelayer to function as an electrical connector, including as an integralpart of the flexible circuit board (e.g., wherein the conductive contactlayer is a not distinct layer, per se).

In some embodiments, the conductive contact layer 1028 includes aconductive material that only conducts in the z-axis. In one exemplaryembodiment, the conductive material is a z-axis conductive film used toelectrically connect the sensor body to the sensor electronics andincludes an anisotropic conductor material, for example, a filmincluding anisotropic electrical conductivity, i.e., z-axisconductivity, with little or no conductivity in the other directions. Inthis exemplary embodiment, discrete electrical contacts are notrequired, and instead, a piece of this anisotropic conductor material toconduct multiple isolated signals (e.g., for each electrode) isprovided.

One example of a suitable Z-axis conductive film useful in accordancewith the some embodiments is a synthetic resin membrane havingnanometer-sized pores extending through the film from one membranesurface to the other surface and having at least some of its poresfilled with a conductive material or composition, such as gold or othermetals, or with one or more nonmetallic conductive materials. The Z-axisconductive film may have a thickness of from about 0.0002 or less,0.0003 inches, 0.0004 inches, or 0.0005 inches to about 0.001 inches,0.0025 inches, 0.005 inches, or 0.01 inches or more. The dimensions ofthe film and the metal fibrils provide good performance at 50 GHz andhigher frequencies. U.S. Pat. No. 5,805,426 describes some z-axisconductive films suitable for use in certain embodiments.

Another example of suitable z-axis electrical conductor films that canbe formed as adhesive and/or in standalone forms and can be made fromnickel particles (e.g., one per conduction path) and a polymer matrix(e.g., polyvinylidene fluoride for the standalone film and epoxy for theadhesive film), such as described in (see, e.g., Yunsheng Xu and D. D.L. Chung, Journal of Electronic Materials, Volume 28, Number 11, pp.1307-1313 (1999)).

In some embodiments, the sensor electronics are located on asubstantially planar, flexible substrate. In some embodiments, thelaminate sensor housing includes a flexible circuit board, such asdescribed in more detail elsewhere herein, on which at least a portionof the sensor electronics are located. The flexible circuit board is atleast one of disposed in the adhesive layer, disposed on the adhesivelayer, and laminated to the adhesive layer, however other configurationsare possible. In some embodiments, the flexible circuit board may be nomore than about 0.2, 0.1, 0.05, 0.04, 0.03, 0.02 or 0.01 inches in itssmallest dimension. In some embodiments, the flexible circuit board iscombined into another functional layer of the laminate housing; forexample, it may not be a distinct layer, per se.

In some embodiments, the laminate sensor housing includes a housingcover 1054 configured to assist in and/or provide at least one of waterresistant, waterproof, and/or hermetically sealed properties to thesensor housing; however, other portions (e.g., layers) of the laminatehousing can additionally include configurations and arrangements thatprovide water resistant, waterproof, and/or hermetically sealedproperties. Additionally or alternatively, the housing cover isconfigured to provide mechanical and/or adhesive force for layers of thelaminate housing. Additionally or alternatively, the housing coverincludes an overcover-type bandage configured to cover some or allportions of the sensor housing and/or adhesive of the device.

In some embodiments, the sensor housing includes an antenna configuredfor radiating or receiving an RF transmission, wherein the antenna islocated on a substantially planar, flexible substrate. In someembodiments, an antenna is at least one of disposed in the adhesivelayer, disposed on the adhesive layer, and laminated to the adhesivelayer, however other configurations are possible. For example, theantenna can be located within any layer of the laminate sensor housing.Alternatively, the sensor body can be configured to communicate withanother device (e.g., a receiver) using other communications systems andmethods, including but not limited to wired connectivity, IR, and thelike. While not wishing to be bound by theory, it is believed that adisposable thin laminate sensor housing as described herein can reduceor eliminate motion artifact caused by external influences (e.g.,bumping or other movement of the sensor housing), which in conventionalsensor systems (e.g., having sensor housing with lower aspect ratiosand/or greater thicknesses) is translated to the sensor body in vivo,causing motion artifact on the sensor signal. Accordingly, a more stablesignal with overall improved patient comfort can be achieved with a thinlaminate sensor housing as described herein.

Sensor Electronics Unit

FIG. 11 is a block diagram illustrating one embodiment of the sensorelectronics unit 590, 1100. In this embodiment, the ASIC 1005 is coupledto a communication port 1138 and a battery 1134. Although theillustrated embodiment includes an Application Specific IntegratedCircuit (ASIC) 1105 that includes much of the electronic circuitry, inother embodiments, the ASIC 1105 is replaced with one or more of anysuitable logic device, such as, for example, field programmable gatearrays (FPGA), microprocessors, analog circuitry, or other digital oranalog circuitry.

In the embodiment shown in FIG. 11, a potentiostat 1110 is coupled to ananalyte sensor in order to receive sensor data from the analyte sensor.Any of a variety of mechanisms can be used to couple the potentiostat1110 to the analyte sensor. For example, in one embodiment, the one ormore ends of the working electrode(s) is exposed to provide electricalconnection between the potentiostat and the first and second sensorelements. In one embodiment, the potentiostat 1110 provides a voltage tothe analyte sensor in order to bias the sensor to enable measurement ofa current value indicative of the analyte concentration in the host(also referred to as the analog portion). The potentiostat can have onechannel or multiple channels, depending on the number of workingelectrodes, for example. In some embodiments, the potentiostat 1110includes a resistor (not shown) that translates the current intovoltage. In some embodiments, a current to frequency converter isprovided that is configured to continuously integrate the measuredcurrent, for example, using a charge counting device. In someembodiments, an A/D converter digitizes the analog signal into “counts”for processing. Accordingly, the resulting raw data stream in counts isdirectly related to the current measured by the potentiostat 1110.

A processor module 1114 is the central control unit that controls theprocessing of the sensor electronics unit. In some embodiments, theprocessor module 1114 is formed as part of a custom chip, such as anASIC, however a computer system other than an ASIC can be used toprocess data as described herein, for example a microprocessor can beused for some or all of the sensor electronics module processing. Theprocessor module 1114 typically provides a program memory 1116, whichprovides semi-permanent storage of data, for example, storing data suchas sensor identifier (ID) and programming to process data streams (forexample, filtering, calibration, fail-safe checking, and the like). Theprocessor additionally can be used for the system's cache memory, forexample for temporarily storing recent sensor data. In some embodiments,the processor module comprises memory storage components such as ROM,RAM, dynamic-RAM, static-RAM, non-static RAM, EEPROM, rewritable ROMs,flash memory, and the like. In one exemplary embodiment, RAM 1118 can beused for the system's cache memory, for example for temporarily storingrecent sensor data.

In some embodiments, the processor module 1114 comprises a digitalfilter, for example, an IIR or FIR filter, configured to smooth the rawdata stream from the A/D converter. Generally, digital filters areprogrammed to filter data sampled at a predetermined time interval (alsoreferred to as a sample rate). In some embodiments, such as when thepotentiostat 1110 is configured to measure the analyte at discrete timeintervals, these time intervals determine the sample rate of the digitalfilter. In some alternative embodiments, wherein the potentiostat 1110is configured to continuously measure the analyte, for example, using acurrent-to-frequency converter, the processor module 1114 can beprogrammed to request a digital value from the integrator at apredetermined time interval, also referred to as the acquisition time.In these alternative embodiments, the values obtained by the processormodule 1114 are advantageously averaged over the acquisition time duethe continuity of the current measurement. Accordingly, the acquisitiontime determines the sample rate of the digital filter.

In one embodiment, the processor module 1114 is further configured togenerate data packages for transmission to one or more display devices.Furthermore, the processor module 1114 generates data packets fortransmission to these outside sources, e.g., via telemetry. As discussedabove, the data packages can be customizable for each display device,for example, and may include any available data, such as displayablesensor information having customized sensor data or transformed sensordata, sensor/sensor electronics module ID code, raw data, filtered data,calibrated data, rate of change information, trend information, errordetection or correction, or the like.

A data storage memory 1120 is operably connected to the processor module1114 and is configured to store a variety of sensor information. In someembodiments, the data storage memory stores 1, 3, 4, 5, 6, 7, 8, 9, 11,11, 12, 13, 14, 15, 20, 30 or more days of continuous analyte sensordata. In some embodiments, the data storage memory 1120 stores sensorinformation such as raw sensor data (one or more raw analyteconcentration values), transformed sensor data, or any other displayablesensor information.

In some embodiments, the sensor electronics unit is configured toreceive and store contact information in the data storage memory (orprogram memory), including a phone number or email address for thesensor's host or health care providers for the host (e.g., familymember(s), nurse(s), doctor(s), or other health care provider(s)), whichenables communication with a contact person (e.g., via phone, pager ortext messaging in response to an alarm (e.g., a hypoglycemic alarm thathas not been responded to by the host)). In some embodiments, userparameters can be programmed into (or modified in) the data storagememory (or program memory) of the sensor electronics module, via adisplay device such as a personal computer, personal digital assistant,or the like. User parameters may include contact information,alert/alarms settings (e.g., thresholds, sounds, volume, or the like),calibration information, font size, display preferences, defaults (e.g.,screens), or the like. Alternatively, the sensor electronics module canbe configured for direct programming of certain user parameters.

In one embodiment, clinical data of a medical practitioner is uploadedto the sensor electronics unit and stored on the data storage memory1120, for example. Thus, information regarding the host's condition,treatments, medications, etc., can be stored on the sensor electronicsunit and can be viewable by the host or other authorized user. In oneembodiment, certain of the clinical data are included in a data packagethat is transmitted to a display device in response to triggering of analert. The clinical data can be uploaded to the sensor electronics unitvia any available communication protocol, such as direct transmissionvia a wireless Bluetooth, infrared, or RF connection, or via a wired USBconnection, for example. Additionally, the clinical data can be uploadedto the sensor electronics unit via indirect transmission, such as viaone or more networks (e.g., local area, personal area, or wide areanetworks, or the Internet) or via a repeater device that receives theclinical data from a device of the medical practitioner and retransmitsthe clinical data to the sensor electronics module.

Any of a variety of configurations of separate data storage and programmemories can be used, including one or multiple memories that providethe necessary storage space to support the sensor electronic dataprocessing and storage requirements. Accordingly, the described locationof storage of any particular information or programming is not meant tobe limiting, but rather exemplary.

In some embodiments, the sensor electronics unit is configured toperform smoothing or filtering algorithms on the sensor data (e.g., rawdata stream or other sensor information), wherein the smoothed orfiltered data is stored in the data storage memory as transformed data.Co-pending U.S. Patent Application Publication No. US-2005-0043598-A1,U.S. Patent Application Publication No. US-2007-0032706-A1, U.S. PatentApplication Publication No. US-2007-0016381-A1 and U.S. PatentApplication Publication No. US-2008-0033254-A1, each of which isincorporated herein by reference in its entirety, describe somealgorithms useful in performing data smoothing or filtering herein(including signal artifacts replacement).

In some embodiments, the sensor electronics unit is configured tocalibrate the sensor data, and the data storage memory 1120 stores thecalibrated sensor data points as transformed sensor data. In somefurther embodiments, the sensor electronics unit is configured towirelessly receive calibration information from a display device, fromwhich the sensor electronics module is configured to calibrate thesensor data. U.S. Pat. Nos. 7,310,544 and 6,931,327, each of which isincorporated herein by reference in its entirety, describe somealgorithms useful in sensor calibration herein.

In some embodiments, the sensor electronics unit is configured toperform additional algorithmic processing on the sensor data (e.g., rawdata stream or other sensor information) and the data storage memory1120 is configured to store the transformed sensor data or sensordiagnostic information associated with the algorithms. U.S. Pat. Nos.7,310,544 and 6,931,327, each of which is incorporated herein byreference in it entirety, describe some algorithms that can be processedby the sensor electronics module.

A user interface 1122 can include any of a variety of interfaces, suchas one or more buttons 1124, a liquid crystal display (LCD) 1126, avibrator 1128, an audio transducer (e.g., speaker) 1130, backlight, orthe like. A backlight can be provided, for example, to aid the user inreading the LCD in low light conditions. The components that comprisethe user interface 1122 provide controls to interact with the user(e.g., the host). One or more buttons 1124 can allow, for example,toggle, menu selection, option selection, status selection, yes/noresponse to on-screen questions, a “turn off” function (e.g., for analarm), a “snooze” function (e.g., for an alarm), a reset, or the like.The LCD 1126 can be provided, for example, to provide the user withvisual data output. The audio transducer 1130 (e.g., speaker) providesaudible signals in response to triggering of certain alerts, such aspresent or predicted hyper- and hypoglycemic conditions. In someembodiments, audible signals are differentiated by tone, volume, dutycycle, pattern, duration, or the like. In some embodiments, the audiblesignal is configured to be silenced (e.g., snoozed or turned off) bypressing one or more buttons 1124 on the sensor electronics module or bysignaling the sensor electronics module using a button or selection on adisplay device (e.g., key fob, cell phone, or the like).

In some embodiments, the audio transducer 1130 is mounted to the circuitboard or the sensor electronics module housing. In some embodiments, thesound produced by the audio transducer 1130 exits the device from asound port in the sensor electronics unit, such as a hole on the sensorelectronics unit. The hole may be waterproofed or otherwise protectedfrom moisture by a waterproof material that easily allows sound wavesthere through. In one embodiment, the hole is protected from moisture byan acoustically transparent venting material (wherein the materialallows at least about 60%, 70%, 80%, 90%, 95%, or more of thetransmitted sound waves therethrough), such as a screw-in vent, apress-fit vent, a snap-in vent, an o-ring vent, and adhesive vent, orthe like. One manufacturer that provides acoustically transparentventing material is W. L. Gore & Associates (Elkton, Md.) under thetrade name Protective Vents (Acoustic Vents).

The vibrator 1128 can include a motor that provides, for example,tactile signals or alerts for reasons such as described with referenceto the audio transducer, above. In one embodiment, the vibrator motor1128 provides a signal in response to triggering of one or more alerts,which can be triggered by the processor module 1114 that processesalgorithms useful in determining whether alert conditions associatedwith one or more alerts have been met, for example, present or predictedhyper- and hypoglycemic conditions. In some embodiments, one or moredifferent alerts are differentiated by intensity, quantity, pattern,duration, or the like. In some embodiments, the alarm is configured tobe silenced (e.g., snoozed or turned off) by pressing one or morebuttons 1124 on the sensor electronics unit or by signaling the sensorelectronics unit using a button or selection on a display device (e.g.,key fob, cell phone, or the like).

In some embodiments, the vibrator motor 1128 is mounted to the circuitboard or the sensor electronics housing. The diameter of the motor maybe less than or equal to about 6 mm, 5 mm, 4 mm, 3.5 mm, 3 mm, 2.5 mm,or 2 mm. The overall length of the vibrator motor may be less than orequal to about 18 mm, 16 mm, 14 mm, 12 mm, or 10 mm. By providing a lowpower vibrator motor, the motor can be placed in the sensor electronicsunit without significantly affecting the low profile nature of theon-skin sensor electronics unit. In some embodiments, the vibrator motor1128 is used to provide a vibratory alarm that creates vibration ormovement of the sensor within the host.

In another alternative embodiment, the sensor electronics unit isconfigured to transmit sound waves into the host's body (e.g., abdomenor other body part) that are felt by the host, thereby alerting the hostwithout calling attention to the host, or allowing a hearing-impairedvisually-impaired, or tactilely-impaired host to be alerted. In someembodiments, the sound waves are transmitted into the host's body usingthe electrodes of the sensor itself. In some embodiments, one or moretranscutaneous electrodes (other than the electrodes related to analytemeasurement) are provided for transmitting sound waves. In someembodiments, electrodes are provided in the adhesive patch that holdsthe sensor/sensor electronics module onto the host's body, which can beused to transmit the sound waves. In some embodiments, different soundwaves are used to transmit different alarm conditions to the host. Thesound waves can be differentiated by any sound characteristic, such asbut not limited to amplitude, frequency and pattern.

In another alternative embodiment, mild electric shock can be used totransmit one or more alarms to the host. The level of shock deliveredmay correspond to a level that is not overly uncomfortable to the host;however, the intensity of the level of shock can be configured toincrease when a host does not respond to (e.g., snooze or turn off) analert within an amount of time. In some embodiments, the shock isdelivered to the host's body using the electrodes of the sensor itself.In some embodiments, the sensor device includes one or more additionalelectrodes configured for delivering the shock to the host (alone or incombination with the electrodes related to analyte measurement). Instill another example, the one or more electrodes are disposed on thehost's skin, such as in the adhesive patch, for delivering the shock.Alternatively, one or more additional patches, each including anelectrode, are provided, for delivering the shock. The additionalpatches can be in wired or wireless communication with the sensorelectronics module.

A telemetry module 1132 is operably connected to the processor module1114 and provides the hardware, firmware, and/or software that enablewireless communication between the sensor electronics unit and one ormore display devices. A variety of wireless communication technologiesthat can be implemented in the telemetry module 1132 include radiofrequency (RF), infrared (IR), Bluetooth, spread spectrum communication,frequency hopping communication, ZigBee, IEEE 802.11/802.16, wireless(e.g., cellular) telecommunication, paging network communication,magnetic induction, satellite data communication, GPRS, ANT, or thelike. In one embodiment, the telemetry module comprises a Bluetoothchip. In some embodiments, Bluetooth technology is implemented in acombination of the telemetry module 1132 and the processor module 1114.

A battery 1134 is operatively connected to the processor module 1114(and possibly other components of the sensor electronics unit) andprovides the necessary power for the sensor electronics unit. In oneembodiment, the battery is a Lithium Manganese Dioxide battery, howeverany appropriately sized and powered battery can be used (e.g., AAA,Nickel-cadmium, Zinc-carbon, Alkaline, Lithium, Nickel-metal hydride,Lithium-ion, Zinc-air, Zinc-mercury oxide, Silver-zinc, orhermetically-sealed). In some embodiments the battery is rechargeable.In some embodiments, a plurality of batteries is used to power thesystem.

A battery charger or regulator 1136 can be configured to receive energyfrom an internal or external charger. In one embodiment, a batteryregulator (or balancer) 1136 regulates the recharging process bybleeding off excess charge current to allow all cells or batteries inthe sensor electronics module to be fully charged without overchargingother cells or batteries. In some embodiments, the battery 1134 (orbatteries) is configured to be charged via an inductive or wirelesscharging pad. Any of a variety of known methods of charging batteriescan be employed, which can be implemented with the system describedherein, including wired (cable/plug) and wireless methods.

One or more communication ports 1138, also referred to as externalconnector(s), can be provided to allow communication with other devices,for example a PC communication (com) port can be provided to enablecommunication with systems that are separate from, or integral with, thesensor electronics module. The communication port, for example, cancomprise a serial (e.g., universal serial bus or “USB”) communicationport, allows for communicating with another computer system (e.g., PC,personal digital assistant or “PDA”, server, or the like). In oneexemplary embodiment, the sensor electronics unit is able to transmithistorical data to a PC or other computing device for retrospectiveanalysis by a patient or physician.

In some continuous analyte sensor systems, the processor module of thesensor electronics unit and/or another computer system is configured toexecute prospective algorithms used to generate transformed sensor dataor displayable sensor information, including, for example, algorithmsthat: evaluate a clinical acceptability of reference or sensor data,evaluate calibration data for best calibration based on inclusioncriteria, evaluate a quality of the calibration, compare estimatedanalyte values with time corresponding measured analyte values, analyzea variation of estimated analyte values, evaluate a stability of thesensor or sensor data, detect signal artifacts (noise), replace signalartifacts, determine a rate of change or trend of the sensor data,perform dynamic and intelligent analyte value estimation, performdiagnostics on the sensor or sensor data, set modes of operation,evaluate the data for aberrancies, or the like, which are described inmore detail in U.S. Pat. Nos. 7,310,544, 6,931,327, U.S. PatentApplication Publication No. US-2005-0043598-A1, U.S. Patent ApplicationPublication No. US-2007-0032706-A1, U.S. Patent Application PublicationNo. US-2007-0016381-A1, U.S. Patent Application Publication No.US-2008-0033254-A1, U.S. Patent Application Publication No.US-2005-0203360-A1, U.S. Patent Application Publication No.US-2005-0154271-A1, U.S. Patent Application Publication No.US-2005-0192557-A1, U.S. Patent Application Publication No.US-2006-0222566-A1, U.S. Patent Application Publication No.US-2007-0203966-A1 and U.S. Patent Application Publication No.US-2007-0208245-A1, each of which is incorporated by reference herein inits entirety. Furthermore, the sensor electronics unit can be configuredto store the transformed sensor data (e.g., values, trend information)and to communicate the displayable sensor information to a plurality ofdifferent display devices. In some embodiments, the display devices are“dummy” devices, namely, they are configured to display the displayablesensor information as received from the sensor electronics unit, withoutany additional sensor data processing.

As described elsewhere herein, in some embodiments, the sensor devicemay comprise a sensor electronics unit that is united with the mountingunit. Alternatively, as illustrated in FIGS. 5D and 5E, the sensorelectronics unit 590 may be detachably connected to the mounting unit ofthe sensor device 500 via a tethered connection to enable the host toremove the sensor electronics unit 590 during activities such asshowering, swimming, or exercising. The tethered configuration may bedesirable in some instances because it isolates any movement, pressure,and other artifacts associated with the sensor electronics unit 590 fromthe sensor device 500. Accordingly, with a tethered configuration, therisk any of the aforementioned artifacts being translated to theelectrode is reduced (or eliminated), as compared to what may occur ifthe sensor electronics unit was directly connected to the electrodes. Asillustrated in FIG. 5F, in some embodiments, a plurality of sensordevices 502, 504 may be connected to the sensor electronics unit 590. Infurther embodiments, one or more of the sensor device may each beassociated with a working electrode, and another sensor device may beassociated with a reference electrode. Alternatively, each of theplurality of sensor devices may each comprise a working and referenceelectrode.

FIG. 12 illustrates another embodiment of a sensor system comprising aplurality of sensor devices. Unlike the embodiment illustrated in FIG.5F, in this particular embodiment, the individual sensor devices 1210are each attached to a laminate 1220 that may comprise sensorelectronics, and are thereby grouped together to form a sensor array1200. Alternatively or additionally, the laminate 1220 may comprise atransmitter configured to transmit sensor data to a remote computersystem. Transmission of sensor data to a remote computer system can beperformed wirelessly or alternatively via a tether that provideselectrical connection between the sensor and the sensor electronicsunit. The laminate 1220 may comprise a plurality of layers, including anadhesive layer for adhering the laminate to the skin. In certainembodiments, the laminate 1220 and the sensor array 1200 may bedisposable and configured for single use. The top surface of thelaminate 1220 may be provided with markings located on top of theplurality of sensor devices 1210, so that a user can see where pressureshould be applied to insert the sensor devices 1210 through the skin.Additional details of the laminate are described elsewhere herein andinclude description corresponding to the laminate shown in FIGS. 10A and10B.

In some embodiments, the plurality of sensor devices 1210 are configuredto be substantially equivalent and can collectively provide an abilityto carry out parallel measurements in a certain region of the host'stissue. Parallel measurements provide redundancy and can increase theaccuracy and reliability of the overall measurement, as the plurality ofmeasurements can be processed (e.g., by averaging the plurality ofmeasurements and/or by eliminating outlier measurements that deviatefrom the average by a predetermined value).

In other embodiments, the sensor devices of the sensor array may differin a variety of characteristics, other than a difference in theinsertion site. For example, some of the sensor devices of the array maybe tuned to detect analyte at low analyte concentrations, while othersensor devices of the same array may be tuned to detect analyte at highanalyte concentrations. As another example, different sensor devices ofthe sensor array may be configured to penetrate the skin at differentpreselected depths and reside in different layers (e.g., the stratumgerminativum, dermis, subcutaneous layers) of the skin. In someembodiments, certain sensor devices 1210 may be used to detect differentanalytes. For example, one or more of the sensor devices 1210 of thearray 1200 may be configured to detect glucose, while other sensordevices 1210 may be used to detect lactic acid, uric acid, or otheranalytes. In some embodiments, the sensor array 1200 is configured toprovide physiological information from different localities of the body,for example, information relating to wound healing, lactic acid inmuscles, presence of interferents, cardiac monitoring, etc. Theinformation collected from the different sensor devices 1210, in turn,may be processed (e.g., as input in an algorithm to trigger calibration,to update calibration, and/or to validate or reject inaccurate referenceanalyte values from a reference analyte monitor) to generate an analyteconcentration value that can be displayed to the user. Other informationthat may be collected include those corresponding to parameters that canaffect sensor characteristics (e.g., sensor sensitivity or baseline).

In some embodiments, the information collected from the plurality ofsensor devices 1210 can be used to provide a basis for determining whichof the sensor devices 1210, in the array 1200, is likely to provide amore representative or accurate analyte measurement. For instance, if acertain number of sensor devices 1210 within a locality of the array1200 provide measurements that are more consistent (e.g., with lessstandard deviation) with each other than sensor devices 1210 of otherlocalities, this information may be processed such that a higherconfidence level is attributed to that particular locality. In turn,averaging of sensor device measurements may take into account thisinformation by according more weight to measurement values from sensordevices 1210 associated with that particular locality than measurementsfrom other sensor devices 1210 associated with other localities.

Alternatively, the plurality of sensor devices 1210 may be used toprovide information regarding differences of a certain parameter along aplane of an area covered by the sensor array 1200. The parameter may berelated to physiological information, such as analyte concentration, sothat an analyte concentration gradient can be measured. In one example,the sensor array 1200 may be configured to detect a build up of lacticacid in a certain locality (e.g. in certain muscles) as a result ofexercise. Knowledge of lactic acid levels can allow a person (e.g., anathlete competing in a long distance running event) to determine and seta target pace (e.g., a certain running pace to achieve a goal time). Asanother example, the parameter may be related to the concentration of adrug, so that the body absorption rate of a drug can be determined.

In certain embodiments, one or more of the sensor devices 1210 mayfunction as a reference electrode and/or one or more of other sensordevices 1210 may function as a counter electrode. In still otherembodiments, a portion of the laminate (e.g., a portion contacting theskin) may be used as the reference electrode or counter electrode.

In some embodiments, the sensor device may include a skin tensioner thatpresses against a skin surface to create tension in the skin surface.FIGS. 13A and 13B illustrate cross-sectional side views one suchembodiment, with FIG. 13A representing a tensioned configuration of thesensor device 1310 prior to deployment and FIG. 13B representing arelaxed configuration after deployment. As shown, the sensor device 1310is equipped with a skin tensioner 1370 that allows the skin surface 1330to be placed under substantially uniform or even tension across acertain skin area covered by the skin tensioner 1370. Skin tensioningprior to sensor device insertion may result in a more stable insertionwith minimal lateral movement of a portion of the senor device that isto be inserted under the skin. In turn, this may further reducediscomfort to the user. In some embodiment, the skin tensioner 1370 maybe formed of any of variety of flexible material (e.g., silicone,polyurethane, neoprene) that possesses flexibility and allows it toconform to the contour of the skin surface 1330. In other embodiments,however, the skin tensioner may be formed of a rigid material.

As illustrated in FIGS. 13A and 13B, the skin tensioner 1370 may beformed of a protruding element that is configured to flex outwardly whenpressed against the skin surface 1330. Although shown to protrudeoutwardly at an angle α of about 135 degrees with respect to the lowersurface of the sensor device 1310 prior to contact with the skin surface1330, it is contemplated that the skin tensioner 1370 may protrude atany angle that is greater than 90 degrees and less than 180 degrees withrespect to the lower surface of the sensor device 1310. In someembodiments, the angle α may be from 100 degrees to 170 degrees, or from115 degrees to 155 degrees, or from 125 to 145 degrees. The skintensioner 1370 may be configured to define an area resembling any of avariety of shapes. In one embodiment, the skin tensioner defines a shapesubstantially resembling a circle. However, it is contemplated that inother embodiments, the skin tensioner may define a shape that resemblesan ellipse, a square, a rectangle, or any other shape that forms anenclosure.

During use, when the sensor device 1310 is placed on the skin surface1330, a pocket 1360 containing air is formed. As pressure (e.g., by auser) is applied to the sensor device 1310 in a direction toward theskin surface 1330, some of the air in the pocket 1360 escapes, therebycreating a relative negative pressure in the pocket. As a result, theskin tensioner 1370 allows the sensor device 1310 to be more securelyheld against the skin surface 1330. In further embodiments, the skintensioner may be equipped with a vacuum mechanism that allows air to besuctioned from the air pocket formed when the skin tensioner 1370 isapplied to the skin surface 1330. In one embodiment, the vacuummechanism may comprise a unidirectional air valve that releases air fromthe pocket when downward pressure is applied to the sensor device. Asair is suctioned out of the pocket 1360, the skin surface 1330 isstretched and may also be pulled upwards toward a piercing needle 1354of the sensor device 1310.

As illustrated in FIGS. 13A and 13B, the sensor device 1310 comprises aspiral spring 1320, a sensor insertion guide 1340, a retainer 1350, andthe above-described skin tensioner 1370. One end of the spiral spring1320 forms an in vivo portion 1322 configured for insertion under theskin surface 1330. The rest of the sensor device 1310 is configured toremain above the skin surface 1330. The spiral spring 1320 may be formedof a material having a high spring constant. During manufacturing, thespiral spring 1320 is tensioned and the in vivo portion is placed intothe sensor insertion guide 1340 to prevent buckling during insertion.The retainer 1350 keeps the sensor 1310 device in the tensioned state,i.e., in a loaded state. During use, after the sensor device 1310 hasbeen affixed to the skin, such that the sensor device 1310 is ready forinsertion, the retainer 1350 is removed (e.g., by pulling out a tab). Asa result of the tension/spring force, the in vivo portion 1322 of thesensor device 1310 is inserted through the skin surface 1330 via thesensor insertion guide 1340.

FIGS. 14A, 14B, and 14C illustrate another embodiment of a sensor device1410 that comprises a skin tensioner 1470. As illustrated in FIG. 14A,the sensor device 1410 also comprises a sensor insertion guide 1440 thataccommodates a sensor unit 1450, which comprises an in vivo portion 1422designed for placement beneath the skin surface 1430. During use, thesensor device 1410 is first affixed to the skin surface 1430, asillustrated in FIG. 14B. Next, the sensor unit 1450 is pushed downwardsto cause deployment, as illustrated in FIG. 14C. This can be achieved inany of a variety of ways. For example, in some embodiments, the downwardpush may originate from action by a user applying pressure directly(e.g., by pushing a button) on the sensor unit 1450. In otherembodiments, the downward push may originate from user action inattaching a certain component (e.g., a transmitter, a sensor electronicsunit) onto the sensor device 1410.

In some embodiments, the sensor device may incorporate Micro ElectroMechanical Systems (MEMS)-based technology, which allow forminiaturization of devices that are minimally invasive. Usingsemiconductor manufacturing techniques, MEMS technology permits a highlevel of functionality to be packaged into a microneedle. Anotheradvantage of employing MEMS technology is that it permits building ofthe sensor device on a wafer scale, which can reduce the number of stepsrequired during manufacturing.

FIG. 15A depicts one embodiment of a sensor device 1510 built based onMEMS technology. The sensor device 1510 includes a sensor body 1590 thatcan be formed of a semiconductor material (e.g. silicon). The sensordevice 1510 also includes an in vivo portion 1560 that comprises aworking electrode 1522, a support member 1530, and a reference electrode1524. Insulation to prevent an electrical connection between the workingelectrode 1522 and the reference electrode 1524 can be achieved bythermal oxidation of the silicon to produce a thin layer of oxide on thesurface of the sensor body 1590. Additionally or alternatively, aninsulating material (e.g., silicon carbide, polyimide) may be depositedonto the sensor body 1590 to provide insulation. The ex vivo portion1570 of the sensor device 1510 comprises a needle base 1516 thatcomprises a contact 1558 for providing an electrical connection betweenthe working electrode 1522 and a sensor electronics unit.

The working electrode 1522 comprises a tissue piercing element 1512which includes a sharp distal tip. The working electrode 1522 may beformed by patterning a thin film layer of conductive material (e.g.,platinum) using known micro-electronic manufacturing methods (e.g.,photolithography, sputtering, and epitaxy). As shown in FIG. 15B, whichprovides a close-up view of the working electrode 1522, the workingelectrode 1522 is formed in a recessed portion of the sensor device1510. The recess permits a membrane (not shown) to be deposited ontoworking electrode 1522 and also provides membrane protection so that themembrane is not delaminated or damaged during sensor device insertion.The different layers of the membrane may be deposited using any knowdeposition techniques, such as dipping, spraying, or ink-jet materialdeposition. In some embodiments, instead of (or in addition to) toemploying a recess to provide membrane protection, the membrane may beprotected by encapsulating or embedding the working electrode (and themembrane associated therewith) in an organic, biodegradable material,such as carbohydrate, which are will chemically breakdown in aphysiological environment. However, it is contemplated that in otherembodiments, inorganic materials (e.g., a gold foil) that can bedissolved by application of a small amount of current can be used toseal off and to protect the membrane during sensor device insertion. Thereference electrode 1524 can be formed by applying a layer of conductivematerial, such as a silver-containing material, for example, onto aportion of the sensor device 1510 not electrically connected to theworking electrode 1522. Alternatively, the reference electrode can beprovided by the application of a conductive material on the back of thesensor device. Although shown in FIG. 15A as being located in the invivo portion 1560 of the sensor device 1510, in certain embodiments, thereference electrode may exist in an ex vivo portion 1570 of the sensordevice 1510, for example, at a location that contacts the skin surface.Although not shown, it is contemplated that in some embodiments, acounter electrode formed of a conductive material (e.g., platinum) maybe employed in addition to or in place of the reference electrode 1524.

FIG. 16 illustrates still another embodiment of a sensor device 1610built based on MEMS technology. In this particular embodiment, theworking electrode 1622 is disposed on the sensor body 1690, instead ofon a tissue piercing element. As shown, portion of the sensor body 1690onto which the working electrode 1622 is disposed is recessed withrespect to the tissue piercing element 1612 of the sensor device 1610.Thus, a membrane (not shown) that is deposited/formed over the workingelectrode 1622 can be protected from delamination during the sensorinsertion process.

FIG. 17A illustrates still another embodiment of the sensor device 1710built based on MEMS technology. The embodiment illustrated in FIG. 17Ais distinguished from the embodiment illustrated in FIG. 16 in that thesensor body 1790 comprises posts 1792 that project outwardly from thesensor body's 1790 surface, which can form the working electrode 1722 orsupport a conductive material deposited thereon that forms the workingelectrode. FIG. 17B is a cross-sectional side view along lines 17B-17Bof FIG. 17A. As illustrated in FIG. 17B, the membrane 1794 may bedisposed onto the working electrode 1722 and protected by posts 1792from delamination during the sensor insertion process.

Remote Computer System

In some embodiments, the sensor data can be transmitted wirelessly to aremote computer system. The wireless transmission may be a RF link (e.g.Bluetooth, Wi-Fi, cellular, etc.) between the remote computer system andthe sensor electronics and may be one- or two-way. The remote computersystem can include any of a variety of devices that facilitates orallows for further processing and/or display of the sensor data, such asfor example, a reader that interrogates the sensor electronics todownload sensor data, a recorder, a database, a sensor receiver, apersonal digital assistant (PDA), an MP3 player, a docking station, apersonal computer (PC) or laptop, a work station, an insulin pump,and/or the like. Additionally or alternatively, sensor data can betransmitted to a remote computer system via a wired link such as by acable (e.g. LAN or USB cable, etc.).

In some embodiments, the remote computer system provides much of theprocessing and display of the sensor data, and can be selectively wornand/or removed at the host's convenience. Thus, the sensor system can bediscreetly worn, and the receiver, which may provide much of theprocessing and display of the sensor data, can be selectively wornand/or removed at the host's convenience. The remote computer system mayinclude programming for retrospectively and/or prospectively initiatinga calibration, converting sensor data, updating the calibration,evaluating received reference and sensor data, and evaluating thecalibration for the analyte sensor, such as described in greater detailwith reference to U.S. Patent Publication No. US-2005-0027463-A1, whichis incorporated herein by reference in its entirety.

Methods of Manufacture

The embodiments of the sensor device described herein may bemanufactured using any of a variety of processes. In some embodiments,the sensor unit, which may comprise the sensor, the tissue piercingelement, and/or the support member, may be formed of a unitary piece,e.g., formed from a wire, a planar substrate, or any other types ofelongated bodies. An etching process can be used to remove certainportions of the elongated body to create electroactive surfaces thereon,thereby forming recessed regions or window regions/surfacescorresponding to working electrodes. The etching process may compriseany of a variety of techniques, such as chemical etching, laserablation, grit blasting, or other similar techniques. In someembodiments, portions of the elongated body can be masked prior to theetching process to define the boundaries of the electroactive surfaces.After the etching process, a membrane comprising an enzyme can bedeposited onto the elongated body using any of a variety of other typesof coating processes, such as a dip coating, spray coating, or vapordeposition, for example. Thereafter, the elongated body may be cleanedand cut for singulation into individual sensor units. Any of a varietyof known cutting mechanisms, such as a hydraulic cutting device, forexample, can be used for the singulation process. In certainembodiments, the elongated body can undergo a surface treatment process(e.g., plasma treatment). After the singulation process, the sensorunits may undergo further processing to sharpen the distal end of thetip of the tissue piercing element and to join other components of thesensor device (e.g., mounting unit, the sensor electronics unit,electrical contacts). It should be understood that the process describedabove is merely exemplary, and some steps may be omitted or replaced byother steps. For example, although the process described above can becarried out by employing a reel-to-reel continuous process, othercontinuous processes or a batch process may also be used. As anotherexample, although in the process described above, the tissue piercingelement, the support member, and/or the sensor are formed of a unitarypiece and collectively form the sensor unit, in other embodiments, thesecomponents may be formed as separate pieces and processed separately.The pieces may then be assembled together to form the sensor unit. Itshould also be understood that although the steps of the method aredescribed in a particular order, the various steps need not be performedsequentially or in the order described.

Kits

The sensor devices according to the embodiments described herein mayoptionally be provided to the user as a kit. The kit can comprise one ormore sensor devices and sensor electronics units packaged in a suitablecontainer. In some embodiments, the sensor device may be substantiallymodular and formed of multiple components (e.g., the tissue piercingelement, the sensor body, the mounting unit, the sensor electronicsunit) that are to be assembled. The kit can also contain an instructionset or user manual with detailed methods of assembling and/or using thekit components.

To the extent publications and patents or patent applicationsincorporated by reference herein contradict the disclosure contained inthe specification, the specification is intended to supersede and/ortake precedence over any such contradictory material.

Terms and phrases used in this document, and variations thereof, unlessotherwise expressly stated, should be construed as open ended as opposedto limiting. As examples of the foregoing, the term “including” shouldbe read to mean “including, without limitation” or the like; the term“comprising” as used herein is synonymous with “including”,“containing”, or “characterized by”, and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm “example” is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; adjectives suchas “known”, “conventional”, “normal”, “standard”, and terms of similarmeaning should not be construed as limiting the item described to agiven time period or to an item available as of a given time, butinstead should be read to encompass known, normal, or standardtechnologies that may be available or known now or at any time in thefuture; and use of terms like “preferred”, “desired”, or “desirable”,and terms of similar meaning should not be understood as implying thatcertain features are critical, essential, or even important to thestructure or function of the invention, but instead as merely intendedto highlight alternative or additional features that may or may not beutilized in a particular embodiment of the invention. Likewise, a groupof items linked with the conjunction “and” should not be read asrequiring that each and every one of those items be present in thegrouping, but rather should be read as “and/or” unless expressly statedotherwise. Similarly, a group of items linked with the conjunction “or”should not be read as requiring mutual exclusivity among that group, butrather should be read as “and/or” unless expressly stated otherwise. Inaddition, as used in this application, the articles “a” and “an” shouldbe construed as referring to one or more than one (i.e., to at leastone) of the grammatical objects of the article. By way of example, “anelement” means one element or more than one element.

The presence in some instances of broadening words and phrases such as“one or more”, “at least”, “but not limited to”, or other like phrasesshould not be read to mean that the narrower case is intended orrequired in instances where such broadening phrases may be absent.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it should be understood that certain changes andmodifications may be practiced. Therefore, the description and examplesshould not be construed as limiting the scope of the invention to thespecific embodiments and examples described herein, but rather to alsocover all modification and alternatives coming with the true scope andspirit of the invention.

What is claimed is:
 1. A direct-press insertion sensor device formeasuring an analyte concentration, the device comprising: a sensorcomprising an in vivo portion of the sensor configured to be insertedthrough a skin of a host, the in vivo portion comprising at least oneelectrode and a membrane covering at least a portion of the at least oneelectrode, and a tissue piercing element integrally formed at a distalend of the sensor, wherein the tissue piercing element is configured topierce the skin of a host, wherein the tissue piercing element has acolumn strength configured to allow insertion of the in vivo portionthrough the skin without substantial buckling; a mounting unitconfigured to support the sensor device on a surface of the skin of thehost, the mounting unit comprising an upper portion comprising aflexible material configured to receive direct pressure from a user forinsertion of the tissue piercing element of the sensor, a lower portioncoupled to an adhesive, the adhesive configured to adhere the mountingunit to the host's skin, and a guiding portion disposed between theupper portion and the lower portion, the guiding portion configured toguide the in vivo portion of the sensor through the skin of the host, alatch member configured to mate with a receiving member, wherein theupper portion is configured to remain in a collapsed state after theinsertion of the in vivo portion by the latch member mating with thereceiving member; and a sensor electronics unit operatively anddetachably connected to the mounting unit.
 2. The sensor device of claim1, wherein the tissue piercing element is configured to withstand anaxial load greater than about 1 Newton without substantial buckling. 3.The sensor device of claim 1, wherein the at least one electrodecomprises a working electrode and a reference electrode.
 4. The sensordevice of claim 1, wherein the sensor electronics unit is configured tobe located over a sensor insertion site.
 5. The sensor device of claim1, wherein the upper portion comprises an elastomeric material.
 6. Thesensor device of claim 1, wherein the in vivo portion has asubstantially circular or oval shape.
 7. The sensor device of claim 1,wherein the upper portion has a domed shape prior to sensor insertion.8. The sensor device of claim 1, wherein the direct pressure is from athumb or finger of a user.
 9. The sensor device of claim 1, wherein themounting unit comprises a self-containing sterile field, wherein priorto sensor insertion the in vivo portion is hidden inside theself-containing sterile field.